Merlin Crossley

Two-timing zinc finger transcription factors liaising with RNA

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1016/J.TIBS.2012.02.001

Abstract: Classical zinc fingers (ZFs) are one of the most common protein domains in higher eukaryotes and have been known for almost 30 years to act as sequence-specific DNA-binding domains. This knowledge has come, however, from the study of a small number of archetypal proteins, and a larger picture is beginning to emerge that ZF functions are far more erse than originally suspected. Here, we review the evidence that a subset of ZF proteins live double lives, binding to both DNA and RNA targets and frequenting both the cytoplasm and the nucleus. This duality can create an important additional level of gene regulation that serves to connect transcriptional and post-transcriptional control.

Homeodomain-Interacting Protein Kinase (HPK-1) regulates stress responses and ageing in C. elegans

Publisher: Springer Science and Business Media LLC

Date: 21-01-2016

DOI: 10.1038/SREP19582

Abstract: Proteins of the Homeodomain-Interacting Protein Kinase (HIPK) family regulate an array of processes in mammalian systems, such as the DNA damage response, cellular proliferation and apoptosis. The nematode Caenorhabditis elegans has a single HIPK homologue called HPK-1. Previous studies have implicated HPK-1 in longevity control and suggested that this protein may be regulated in a stress-dependent manner. Here we set out to expand these observations by investigating the role of HPK-1 in longevity and in the response to heat and oxidative stress. We find that levels of HPK-1 are regulated by heat stress and that HPK-1 contributes to survival following heat or oxidative stress. Additionally, we show that HPK-1 is required for normal longevity, with loss of HPK-1 function leading to a faster decline of physiological processes that reflect premature ageing. Through microarray analysis, we have found that HPK-1-regulated genes include those encoding proteins that serve important functions in stress responses such as Phase I and Phase II detoxification enzymes. Consistent with a role in longevity assurance, HPK-1 also regulates the expression of age-regulated genes. Lastly, we show that HPK-1 functions in the same pathway as DAF-16 to regulate longevity and reveal a new role for HPK-1 in development.

Homeodomain interacting protein kinase (HPK-1) is required in the soma for robust germline proliferation in C. elegans

Publisher: Wiley

Date: 02-09-2013

DOI: 10.1002/DVDY.24023

Abstract: Tightly regulated pathways maintain the balance between proliferation and differentiation within stem cell populations. In Caenorhabditis elegans, the germline is the only tissue that is maintained by stem-like cells into adulthood. In the current study, we investigated the role played by a member of the Homeodomain interacting protein kinase (HIPK) family of serine/threonine kinases, HPK-1, in the development and maintenance of the C. elegans germline. We report that HPK-1 is required for promotion of germline proliferation during development and into adulthood. Additionally, we show that HPK-1 is required in the soma for regulation of germline proliferation. We also show that HPK-1 is a predominantly nuclear protein expressed in several somatic tissues including germline-interacting somatic cells. Our observations are consistent with a conserved role for HIPKs in the control of cellular proliferation and identify a new context for such control in germ cell proliferation.

Human KLF17 is a new member of the Sp/KLF family of transcription factors

Publisher: Elsevier BV

Date: 04-2006

DOI: 10.1016/J.YGENO.2005.12.011

Abstract: The Sp/KLF transcription factors perform a variety of biological functions, but are related in that they bind GC-box and CACCC-box sequences in DNA via a highly conserved DNA-binding domain. A database homology search, using the zinc finger DNA-binding domain characteristic of the family, has identified human KLF17 as a new family member that is most closely related to KLFs 1-8 and 12. KLF17 appears to be the human orthologue of the previously reported mouse gene, zinc finger protein 393 (Zfp393), although it has erged significantly. The DNA-binding domain is the most conserved region, suggesting that both the murine and the human forms recognize the same binding sites in DNA and may retain similar functions. We show that human KLF17 can bind G/C-rich sites via its zinc fingers and is able to activate transcription from CACCC-box elements. This is the first report of the DNA-binding characteristics and transactivation activity of human KLF17, which, together with the homology it displays to other KLF proteins, put it in the Sp/KLF family.

ZNF410 Uniquely Activates the NuRD Component CHD4 to Silence Fetal Hemoglobin Expression

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.MOLCEL.2020.11.006

Modification with SUMO

Publisher: EMBO

Date: 02-2003

DOI: 10.1038/SJ.EMBOR.EMBOR738

Abstract: Small ubiquitin‐related modifier (SUMO) is a protein moiety that is ligated to lysine residues in a variety of target proteins. The addition of SUMO can modulate the ability of proteins to interact with their partners, alter their patterns of subcellular localization and control their stability. It is clear that SUMO influences many different biological processes, but recent data suggest that it is particularly important in the regulation of transcription. Indeed, several transcription factors, such as Sp3, c‐Jun, c‐Myb and various nuclear receptors, have recently been shown to be subject to sumoylation and, although this modification can have a positive influence, a growing body of evidence highlights its role in the negative regulation of transcription. This review summarizes recent experiments focusing on sumoylation and transcriptional repression.

Charting a noncoding gene for γ-globin activation

Publisher: American Society of Hematology

Date: 11-2018

DOI: 10.1182/BLOOD-2018-09-873620

Key residues characteristic of GATA N-fingers are recognized by FOG

Publisher: Elsevier BV

Date: 12-1998

DOI: 10.1074/JBC.273.50.33595

Mammalian Krüppel-like transcription factors: more than just a pretty finger

Publisher: Elsevier BV

Date: 06-1999

DOI: 10.1016/S0968-0004(99)01406-1

Abstract: The transcription factor SP1 contains three Krüppel-like zinc fingers. Recently, several related proteins, including erythroid, lung and gut-enriched Krüppel-like factors, have been identified. Together with SP1, these proteins form a sizeable family of transcription factors that share homology in their zinc-finger domains but differ elsewhere. Analysis of these differences is illuminating specific mechanisms by which transcription is regulated.

KLF3 Regulates Muscle-Specific Gene Expression and Synergizes with Serum Response Factor on KLF Binding Sites

Publisher: Informa UK Limited

Date: 07-2010

DOI: 10.1128/MCB.00302-10

Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin

Publisher: Springer Science and Business Media LLC

Date: 08-2021

DOI: 10.1038/S41588-021-00904-0

The Ikaros family protein Eos associates with C‐terminal‐binding protein corepressors

Publisher: Wiley

Date: 23-11-2002

DOI: 10.1046/J.1432-1033.2002.03313.X

Abstract: Eos is a zinc finger transcription factor of the Ikaros family. It binds typical GGGAA Ikaros recognition sites in DNA and functions as a transcriptional repressor. Here we show that Eos associates with the corepressor C-terminal-binding protein (CtBP). CtBP has previously been shown to bind Pro-X-Asp-Leu-Ser (PXDLS) motifs in several DNA-binding proteins. We note that Eos contains a related motif PEDLA, and we demonstrate that CtBP can bind this site weakly but that it also contacts additional regions of Eos. Consistent with this finding, mutation of the PEDLA motif does not negate CtBP binding or CtBP-mediated repression by Eos. CtBP has previously been shown to bind to a PXDLS-type motif in Ikaros, and we show that another Ikaros-related protein TRPS1 also contains a PXDLS CtBP contact motif within its repression domain. We conclude that several Ikaros family proteins utilize CtBP corepressors to inhibit gene expression.

On the Effects of Local Environment on Active Galactic Nucleus (AGN) in the Horizon Run 5 Simulation

Publisher: American Astronomical Society

Date: 08-2023

DOI: 10.3847/1538-4357/ACDD6B

Abstract: We use the Horizon Run 5 cosmological simulation to study the effect of galaxy intrinsic properties and the local environment on active galactic nuclei (AGNs) characterized by their threshold of the accretion rate. We select galaxies in the stellar mass range 10 9.5 ≤ M * / M ⊙ ≤ 10 10.5 in the snapshot at redshift z = 0.625. Among various intrinsic properties, we find that the star formation rate of the host galaxy is most correlated to the AGN activity. To quantify the environment, we use background galaxy number density (large-scale environment) and distance and morphological type of the nearest neighbors (small-scale environment), and study their relative effects on the AGN properties. We find that, compared to the background density, the nearest neighbor environment is the dominant quantity determining the bolometric luminosity, star formation rate, and kinematic properties of AGNs and better dictates the gas mass of the host galaxy. We show that the cold gas content in the host galaxies is crucial in triggering AGN activity. However, when the nearest neighbor environment effects start to act at the neighbor distance of less than about half the virial radius of the neighbor, the neighbor environmental effects are the most dominant factor for quasar activity.

Expression of the parathyroid Ca²⁺-sensing receptor in cytotrophoblasts from human term placenta

Publisher: Bioscientifica

Date: 03-1998

DOI: 10.1677/JOE.0.1560425

Abstract: Fura-2-loaded human cytotrophoblasts responded to elevated extracellular Ca2+ concentration ([Ca2+]o) with monophasic or, in the case of large ( 20 microns) extravillous cells, biphasic elevations in intracellular free Ca2+ ion concentration ([Ca2+]i) that returned to baseline levels after restoration of control [Ca2+]o. Large extravillous cytotrophoblasts also responded to elevated [Mg2+]o with transient elevations in [Ca2+]i, consistent with the behaviour of the parathyroid Ca2(+)-sensing receptor. Expression of the parathyroid Ca2(+)-sensing receptor in placental cells was confirmed using Northern blot and reverse transcription (RT)-PCR analysis. However, the major transcript in human placental cells (6.2 kb) differed from that expressed by human parathyroid cells (5.6 kb). RT-PCR analysis and DNA sequencing of key PCR products also revealed the presence of a splice variant in placental and parathyroid cells that lacks exon 3.

Assessment of the robustness of a serendipitous zinc binding fold: Mutagenesis and protein grafting

Publisher: Elsevier BV

Date: 02-2005

DOI: 10.1016/J.STR.2004.12.007

Abstract: Zinc binding motifs have received much attention in the area of protein design. Here, we have tested the suitability of a recently discovered nonnative zinc binding structure as a protein design scaffold. A series of multiple alanine mutants was created to investigate the minimal requirements for folding, and solution structures of these mutants showed that the original fold was maintained, despite changes in approximately 50% of the sequence. We next attempted to transplant binding faces from chosen bimolecular interactions onto one of these mutants, and many of the resulting "chimeras" were shown to adopt a native-like fold. These results both highlight the robust nature of small zinc binding domains and underscore the complexity of designing functional proteins, even using such small, highly ordered scaffolds as templates.

Directing an artificial zinc finger protein to new targets by fusion to a non-DNA-binding domain.

Publisher: Oxford University Press (OUP)

Date: 15-12-2015

DOI: 10.1093/NAR/GKV1380

Wake-up Sleepy Gene: Reactivating Fetal Globin for β-Hemoglobinopathies

Publisher: Elsevier BV

Date: 12-2018

DOI: 10.1016/J.TIG.2018.09.004

Abstract: Disorders in hemoglobin (hemoglobinopathies) were the first monogenic diseases to be characterized and remain among the most common and best understood genetic conditions. Moreover, the study of the β-globin locus provides a textbook ex le of developmental gene regulation. The fetal γ-globin genes (HBG1/HBG2) are ordinarily silenced around birth, whereupon their expression is replaced by the adult β-globin genes (HBB primarily and HBD). Over 50 years ago it was recognized that mutations that cause lifelong persistence of fetal γ-globin expression ameliorate the debilitating effects of mutations in β-globin. Since then, research has focused on therapeutically reactivating the fetal γ-globin genes. Here, we summarize recent discoveries, focusing on the influence of genome editing technologies, including CRISPR-Cas9, and emerging gene therapy approaches.

The Caenorhabditis elegans protein CTBP-1 defines a new group of THAP domain-containing CtBP corepressors.

Publisher: Elsevier BV

Date: 2007

DOI: 10.1016/J.JMB.2007.10.041

Abstract: The C-terminal binding proteins (CtBPs) play roles in erse cellular processes including transcriptional regulation, Golgi membrane fission, and synaptic ribbon formation. In the context of transcriptional regulation, they function as corepressors, interacting with promoter-bound transcription factors and recruiting a large protein complex that contains chromatin-modifying enzymes. We recently described the structure of a Thanatos-associated protein (THAP) domain that is found in a new member of the CtBP family, the Caenorhabditis elegans CTBP-1 protein. We have identified additional THAP domain-containing CtBPs in the nematode, echinoderm, and cephalochordate lineages. The distribution of these lineages within the animal kingdom suggests that the ancestral form of the animal CtBPs may have contained a THAP domain that was subsequently lost in the vertebrate and arthropod lineages. We also provide functional data indicating that CTBP-1 represses gene expression and homodimerizes and interacts with PXDLS-containing partner proteins, three key features of the previously characterized animal CtBPs. CTBP-1 is therefore the founding member of a new subgroup within the CtBP corepressor family, the THAP domain-containing CtBPs.

Controlling the size of lipid droplets: Lipid and protein factors

Publisher: Elsevier BV

Date: 08-2012

DOI: 10.1016/J.CEB.2012.05.012

Abstract: Recent advances have transformed our understanding of lipid droplets (LDs). Once regarded as inert lipid storage granules, LDs are now recognized as multi-functional organelles that affect many aspects of cell biology and metabolism. However, fundamental questions concerning the biogenesis and growth of LDs remain unanswered. Recent studies have uncovered novel modes of LD growth (including rapid/homotypic as well as slow/atypical LD fusion), and identified key proteins (e.g. Fsp27, seipin, FITM2 and perilipin 1) and lipids (e.g. phosphatidylcholine and phosphatidic acid) that regulate the size of LDs. Phospholipids appear to have an evolutionarily conserved role in LD growth. Protein factors may regulate LD expansion directly and/or indirectly through modulating the level and composition of phospholipids on LD surface.

A natural regulatory mutation in the proximal promoter elevates fetal globin expression by creating a de novo GATA1 site

Publisher: American Society of Hematology

Date: 21-02-2019

DOI: 10.1182/BLOOD-2018-07-863951

Abstract: β-hemoglobinopathies, such as sickle cell disease and β-thalassemia, result from mutations in the adult β-globin gene. Reactivating the developmentally silenced fetal γ-globin gene elevates fetal hemoglobin levels and ameliorates symptoms of β-hemoglobinopathies. The continued expression of fetal γ-globin into adulthood occurs naturally in a genetic condition termed hereditary persistence of fetal hemoglobin (HPFH). Point mutations in the fetal γ-globin proximal promoter can cause HPFH. The −113A& G HPFH mutation falls within the −115 cluster of HPFH mutations, a binding site for the fetal globin repressor BCL11A. We demonstrate that the −113A& G HPFH mutation, unlike other mutations in the cluster, does not disrupt BCL11A binding but rather creates a de novo binding site for the transcriptional activator GATA1. Introduction of the −113A& G HPFH mutation into erythroid cells using the clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) system increases GATA1 binding and elevates fetal globin levels. These results reveal the mechanism by which the −113A& G HPFH mutation elevates fetal globin and demonstrate the sensitivity of the fetal globin promoter to point mutations that often disrupt repressor binding sites but here create a de novo site for an erythroid activator.

Unscrambling the genome

Publisher: Springer Science and Business Media LLC

Date: 2003

DOI: 10.1186/GB-2003-4-5-320

Abstract: A report on the 24th Annual Lorne Conference on the Organization and Expression of the Genome, Lorne, Victoria, Australia, 16-20 February 2003.

Protein-protein interaction between Fli-1 and GATA-1 mediates synergistic expression of megakaryocyte-specific genes through cooperative DNA binding.

Publisher: Informa UK Limited

Date: 05-2003

DOI: 10.1128/MCB.23.10.3427-3441.2003

Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding

Publisher: Springer Science and Business Media LLC

Date: 04-2018

DOI: 10.1038/S41588-018-0085-0

Abstract: β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia result from mutations in the adult HBB (β-globin) gene. Reactivating the developmentally silenced fetal HBG1 and HBG2 (γ-globin) genes is a therapeutic goal for treating SCD and β-thalassemia

Eosinophil function in adipose tissue is regulated by Krüppel-like factor 3 (KLF3)

Publisher: Springer Science and Business Media LLC

Date: 10-06-2020

DOI: 10.1038/S41467-020-16758-9

Abstract: The conversion of white adipocytes to thermogenic beige adipocytes represents a potential mechanism to treat obesity and related metabolic disorders. However, the mechanisms involved in converting white to beige adipose tissue remain incompletely understood. Here we show profound beiging in a genetic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3). Bone marrow transplants from these animals confer the beige phenotype on wild type recipients. Analysis of the cellular and molecular changes reveal an accumulation of eosinophils in adipose tissue. We examine the transcriptomic profile of adipose-resident eosinophils and posit that KLF3 regulates adipose tissue function via transcriptional control of secreted molecules linked to beiging. Furthermore, we provide evidence that eosinophils may directly act on adipocytes to drive beiging and highlight the critical role of these little-understood immune cells in thermogenesis.

A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor CtBP

Publisher: Wiley

Date: 07-06-2006

DOI: 10.1111/J.1742-4658.2006.05301.X

Abstract: HIC1 (hypermethylated in cancer) is a tumour suppressor gene located in 17p13.3, a region frequently hypermethylated or deleted in many types of prevalent human tumour. HIC1 is also a candidate for a contiguous-gene syndrome, the Miller-Dieker syndrome, a severe form of lissencephaly accompanied by developmental anomalies. HIC1 encodes a BTB/POZ-zinc finger transcriptional repressor. HIC1 represses transcription via two autonomous repression domains, an N-terminal BTB/POZ and a central region, by trichostatin A-insensitive and trichostatin A-sensitive mechanisms, respectively. The HIC1 central region recruits the corepressor CtBP (C-terminal binding protein) through a conserved GLDLSKK motif, a variant of the consensus C-terminal binding protein interaction domain PxDLSxK/R. Here, we show that HIC1 interacts with both CtBP1 and CtBP2 and that this interaction is stimulated by agents increasing NADH levels. Furthermore, point mutation of two CtBP2 residues forming part of the structure of the recognition cleft for a PxDLS motif also ablates the interaction with a GxDLS motif. Conversely, in perfect agreement with the structural data and the universal conservation of this residue in all C-terminal binding protein-interacting motifs, mutation of the central leucine residue (leucine 225 in HIC1) abolishes the interaction between HIC1 and CtBP1 or CtBP2. As expected from the corepressor activity of CtBP, this mutation also impairs the HIC1-mediated transcriptional repression. These results thus demonstrate a strong conservation in the binding of C-terminal binding protein-interacting domains despite great variability in their amino acid sequences. Finally, this L225A point mutation could also provide useful knock-in animal models to study the role of the HIC1-CtBP interaction in tumorigenesis and in development.

Mutations ofZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot

Publisher: Hindawi Limited

Date: 17-11-2003

DOI: 10.1002/HUMU.10308

A rapid method for assessing the RNA-binding potential of a protein

Publisher: Oxford University Press (OUP)

Date: 03-04-2012

DOI: 10.1093/NAR/GKS285

Hemophilia B Leyden and once mysterious cis-regulatory mutations

Publisher: Elsevier BV

Date: 2014

DOI: 10.1016/J.TIG.2013.09.007

Abstract: Hemophilia B is a classic, monogenic blood clotting disease caused by mutations in the coagulation factor IX (F9) locus. Although interpreting mutations within the gene itself has been relatively straightforward, ascribing molecular mechanisms to the complete suite of mutations within the promoter region has proven somewhat difficult and has only recently been achieved. These mutations, which are clustered at discrete transcription factor binding sites, dynamically alter the developmental expression of F9 in different ways. They illustrate how single-nucleotide mutations in cis-regulatory regions can have drastic ramifications for the control of gene expression and in some instances be causative of disease. Here we present the human F9 promoter as a model ex le for which saturation mutation mapping has revealed the mechanisms of its regulation. Moreover, we suggest that the growing number of genome-wide studies of transcription factor activity will accelerate both the discovery and understanding of regulatory polymorphisms and mutations.

New insights into DNA recognition by zinc fingers revealed by structural analysis of the oncoprotein ZNF217

Publisher: Elsevier BV

Date: 04-2013

DOI: 10.1074/JBC.M112.441451

Direct competition between DNA binding factors highlights the role of Krüppel-like Factor 1 in the erythroid/megakaryocyte switch

Publisher: Springer Science and Business Media LLC

Date: 09-06-2017

DOI: 10.1038/S41598-017-03289-5

Abstract: The Krüppel-like factor (KLF) family of transcription factors play critical roles in haematopoiesis. KLF1, the founding member of the family, has been implicated in the control of both erythropoiesis and megakaryopoiesis. Here we describe a novel system using an artificial dominant negative isoform of KLF1 to investigate the role of KLF1 in the erythroid/megakaryocytic switch in vivo . We developed murine cell lines stably overexpressing a GST-KLF1 DNA binding domain fusion protein (GST-KLF1 DBD), as well as lines expressing GST only as a control. Interestingly, overexpression of GST-KLF1 DBD led to an overall reduction in erythroid features and an increase in megakaryocytic features indicative of a reduced function of endogenous KLF1. We simultaneously compared in vivo DNA occupancy of both endogenous KLF1 and GST-KLF1 DBD by ChIP qPCR. Here we found that GST-KLF1 DBD physically displaces endogenous KLF1 at a number of loci, providing novel in vivo evidence of direct competition between DNA binding proteins. These results highlight the role of KLF1 in the erythroid/megakaryocyte switch and suggest that direct competition between transcription factors with similar consensus sequences is an important mechanism in transcriptional regulation.

Regions outside the DNA-binding domain are critical for proper in vivo specificity of an archetypal zinc finger transcription factor.

Publisher: Oxford University Press (OUP)

Date: 07-10-2013

DOI: 10.1093/NAR/GKT895

Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities.

Publisher: Elsevier BV

Date: 12-2000

DOI: 10.1074/JBC.M005457200

Characterization of the conserved interaction between GATA and FOG family proteins

Publisher: Elsevier BV

Date: 09-2002

DOI: 10.1074/JBC.M204663200

The C-terminal Domain of Eos Forms a High Order Complex in Solution

Publisher: Elsevier BV

Date: 10-2003

DOI: 10.1074/JBC.M306817200

HIR4: cosmology from a simulated neutral hydrogen full sky using Horizon Run 4

Publisher: Oxford University Press (OUP)

Date: 05-05-2020

DOI: 10.1093/MNRAS/STAA1191

Abstract: The distribution of cosmological neutral hydrogen will provide a new window into the large-scale structure of the Universe with the next generation of radio telescopes and surveys. The observation of this material, through 21 cm line emission, will be confused by foreground emission in the same frequencies. Even after these foregrounds are removed, the reconstructed map may not exactly match the original cosmological signal, which will introduce systematic errors and offset into the measured correlations. In this paper, we simulate future surveys of neutral hydrogen using the Horizon Run 4 (HR4) cosmological N-body simulation. We generate H i intensity maps from the HR4 halo catalogue, and combine with foreground radio emission maps from the Global Sky Model, to create accurate simulations over the entire sky. We simulate the H i sky for the frequency range 700–800 MHz, matching the sensitivity of the Tianlai pathfinder. We test the accuracy of the fastICA, PCA, and log-polynomial fitting foreground removal methods to recover the input cosmological angular power spectrum and measure the parameters. We show the effect of survey noise levels and beam sizes on the recovered the cosmological constraints. We find that while the reconstruction removes power from the cosmological 21 cm distribution on large scales, we can correct for this and recover the input parameters in the noise-free case. However, the effect of noise and beam size of the Tianlai pathfinder prevents accurate recovery of the cosmological parameters when using only intensity mapping information.

Regulation of the β-globin locus

Publisher: Elsevier BV

Date: 1993

DOI: 10.1016/0959-437X(93)90028-N

Abstract: Transcription of the human beta-globin gene cluster depends upon upstream regulatory sequences, which are collectively termed the locus control region. Recent studies have provided new insights into how the in idual genes of the cluster are regulated through development. The crux of transcriptional activation is how the locus control region communicates with the gene-proximal regulatory elements.

Kruppel-like factors compete for promoters and enhancers to fine-tune transcription

Publisher: Oxford University Press (OUP)

Date: 24-05-2017

DOI: 10.1093/NAR/GKX441

Low-surface-brightness Galaxies are Missing in the Observed Stellar Mass Function

Publisher: American Astronomical Society

Date: 07-2023

DOI: 10.3847/1538-4357/ACD251

Abstract: We investigate the impact of the surface-brightness (SB) limit on the galaxy stellar mass functions (GSMFs) using galaxy catalogs generated from the Horizon Run 5 ( HR5 ) simulation. We compare the stellar-to-halo-mass relation, GSMF, and size–stellar mass relation of the HR5 galaxies with observational data and other cosmological simulations. The mean SB of simulated galaxies are computed using their effective radii, luminosities, and colors. To examine the cosmic SB dimming effect, we compute k -corrections from the spectral energy distributions of in idual simulated galaxy at each redshift, apply the k -corrections to the galaxies, and conduct mock surveys based on the various SB limits. We find that the GSMFs are significantly affected by the SB limits at the low-mass end. This approach can ease the discrepancy between the GSMFs obtained from simulations and observations at 0.6 ≲ z ≤ 2. We also find that a redshift survey with an SB selection limit of μ r e = 25 mag arcsec −2 will miss 20% of galaxies with M ⋆ g = 10 9 M ⊙ at z = 0.625. The missing fraction of low-surface-brightness galaxies increases to 35%, 55%, and 80% at z = 0.9, 1.1, and 1.9, respectively, at the same SB limit.

Partial reprogramming of heterologous cells by defined factors to generate megakaryocyte lineage-restricted biomolecules

Publisher: Elsevier BV

Date: 12-2018

DOI: 10.1016/J.BTRE.2018.E00285

The solution structure of the N-terminal zinc finger of GATA-1 reveals a specific binding face for the transcriptional co-factor FOG

Publisher: Springer Science and Business Media LLC

Date: 1999

DOI: 10.1023/A:1008309602929

Abstract: Zinc fingers (ZnFs) are generally regarded as DNA-binding motifs. However, a number of recent reports have implicated particular ZnFs in the mediation of protein-protein interactions. The N-terminal ZnF of GATA-1 (NF) is one such finger, having been shown to interact with a number of other proteins, including the recently discovered transcriptional co-factor FOG. Here we solve the three-dimensional structure of the NF in solution using multidimensional 1H/15N NMR spectroscopy, and we use 1H/15N spin relaxation measurements to investigate its backbone dynamics. The structure consists of two distorted beta-hairpins and a single alpha-helix, and is similar to that of the C-terminal ZnF of chicken GATA-1. Comparisons of the NF structure with those of other C4-type zinc binding motifs, including hormone receptor and LIM domains, also reveal substantial structural homology. Finally, we use the structure to map the spatial locations of NF residues shown by mutagenesis to be essential for FOG binding, and demonstrate that these residues all lie on a single face of the NF. Notably, this face is well removed from the putative DNA-binding face of the NF, an observation which is suggestive of simultaneous roles for the NF that is, stabilisation of GATA-1 DNA complexes and recruitment of FOG to GATA-1-controlled promoter regions.

Protein-protein interactions: Analysis of a false positive GST pulldown result

Publisher: Wiley

Date: 02-06-2011

DOI: 10.1002/PROT.23068

Abstract: One of the most common ways to demonstrate a direct protein-protein interaction in vitro is the glutathione-S-transferse (GST)-pulldown. Here we report the detailed characterization of a putative interaction between two transcription factor proteins, GATA-1 and Krüppel-like factor 3 (KLF3/BKLF) that show robust interactions in GST-pulldown experiments. Attempts to map the interaction interface of GATA-1 on KLF3 using a mutagenic screening approach did not yield a contiguous binding face on KLF3, suggesting that the interaction might be non-specific. NMR experiments showed that the proteins do not interact at protein concentrations of 50-100 μM. Rather, the GST tag can cause part of KLF3 to misfold. In addition to misfolding, the fact that both proteins are DNA-binding domains appears to introduce binding artifacts (possibly nucleic acid bridging) that cannot be resolved by the addition of nucleases or ethidium bromide (EtBr). This study emphasizes the need for caution in relying on GST-pulldown results and related methods, without convincing confirmation from different approaches.

DNA damage repair and transcription

Publisher: Springer Science and Business Media LLC

Date: 08-2004

DOI: 10.1007/S00018-004-4176-Y

Abstract: In eukaryotes, the packaging of DNA into nucleosomes and the organization of chromatin fibres generate constraints for all nuclear processes involving DNA, including replication, repair, recombination and transcription. The three major processes that regulate chromatin structure and counterbalance its repressive effects are ATP-dependent chromatin remodeling, post-translational modification of histones and histone replacement. While many of these processes have been intensively studied with respect to their effects on transcription, there is also evidence that they affect other nuclear processes involving DNA. This review explores the functions of chromatin-remodeling factors and histone-modifying enzymes in gene regulation and summarizes recent findings which suggest a role for these chromatin modifiers in DNA repair.

KLF1 directly activates expression of the novel fetal globin repressor ZBTB7A/LRF in erythroid cells

Publisher: American Society of Hematology

Date: 25-04-2017

DOI: 10.1182/BLOODADVANCES.2016002303

Abstract: KLF1 directly drives expression of ZBTB7A, a key repressor of fetal γ-globin gene expression, in erythroid cells. An erythroid-specific regulation mechanism allows upregulation of a novel ZBTB7A transcript in erythroid cells.

Classic zinc finger from friend of GATA mediates an interaction with the coiled-coil of transforming acidic coiled-coil 3

Publisher: Elsevier BV

Date: 09-2004

DOI: 10.1074/JBC.M404130200

KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells

Publisher: Springer Science and Business Media LLC

Date: 06-12-2004

DOI: 10.1038/SJ.ONC.1208216

Abstract: A molecular mechanism to explain reduced KAI1 expression in invasive and metastatic tumour cells remains elusive. In this report, we extend an earlier study in bladder cells to confirm that a 76 bp region of the KAI1 promoter (residues -922 to -847), with binding motifs for p53, AP1 and AP2, is required for high level activity of a KAI1 reporter in prostate cancer cell lines. Gel shift and supershift experiments supported binding of p53, junB and heterodimers of AP2alpha/AP2gamma or AP2beta/AP2gamma to this sequence. Introduction of mutations into specific motifs demonstrated an essential requirement for p53 and junB to reporter activity, and that functional synergy between these two factors enhanced activity. A further elevation of reporter activity required AP2. Roles of in idual p53, junB and AP2 proteins, as well as functional synergy between p53 and junB, were confirmed in transfection experiments. Western blotting analysis showed that an absence of wild-type p53, and/or a loss of junB and AP2 protein expression, correlated with downregulation of KAI1 mRNA levels in a series of prostate cancer cell lines. A loss of p53 function and/or expression of junB, combined with reduced expression of specific AP2 proteins may underly downregulated KAI1 expression in tumour cells.

X-linked thrombocytopenia caused by a novel mutation ofGATA-1

Publisher: American Society of Hematology

Date: 11-2001

DOI: 10.1182/BLOOD.V98.9.2681

Abstract: A family with recessive X-linked thrombocytopenia affecting 4 males in 2 generations, characterized by macrothrombocytopenia, profound bleeding, and mild dyserythropoiesis, is described. Microsatellite linkage analysis identified a region of the X chromosome including theGATA-1 gene, which encodes a critical transcription factor involved in erythrocyte and megakaryocyte development. By sequencing the entire coding region of GATA-1, a 2-base mutation was detected that results in a single amino acid substitution (glycine 208 to serine) within a highly conserved portion of the N-terminal zinc finger domain. Restriction fragment length polymorphism confirmed that this novel mutation segregated with the affected males and female carrier. Although not required for DNA binding, Gly208 of GATA-1 is involved in direct interaction with Friend of GATA-1 (FOG), a cofactor required for normal megakaryocytic and erythroid development. These results demonstrate that the GATA-1–FOG interaction is partially disrupted by the mutation and that the greatest effect involves contact with the FOG zinc finger 9. These findings help describe a novel mutation of GATA-1 in humans as a cause of X-linked thrombocytopenia, and they confirm the vital role played by this transcription factor during in vivo megakaryocyte development.

Response to Chatr-aryamontri et al.: Protein interactions: to believe or not to believe?

Publisher: Elsevier BV

Date: 06-2008

DOI: 10.1016/J.TIBS.2008.04.003

Zinc fingers are sticking together

Publisher: Elsevier BV

Date: 1998

DOI: 10.1016/S0968-0004(97)01168-7

Abstract: Tree lycopsids prospered in the Late Devonian and constituted a major part of the Late Paleozoic forest ecosystem that deeply impacted the Earth's climate. However, the fertile organs of these early tree lycopsids display low morphological disparity, which has h ered further knowledge about their ecological habit. Here, we report Omprelostrobus gigas gen. et sp. nov. from the Upper Devonian (Famennian) Wutong Formation at Changxing, Zhejiang, China. The collection includes aerial axes, strobili and associated roots. The strobili are the largest among coeval lycopsids to our knowledge, and are ided into proximal and distal portions by dimorphic sporophylls with differentiated laminae and probable strong photosynthetic capacity. The associated but not attached roots displaying multiple isotomous branches lack rootlets and typical rootlet scars. The varied strobili sizes of early tree lycopsids were relatively independent of their body plan, but the large strobili could suggest increased reproductive investment to overcome the disadvantages of the disturbed flooded habitat.

SUMV-1 antagonizes the activity of synthetic multivulva genes in Caenorhabditis elegans.

Publisher: Elsevier BV

Date: 08-2014

DOI: 10.1016/J.YDBIO.2014.05.018

Abstract: Chromatin regulators contribute to the developmental control of gene expression. In the nematode Caenorhabditis elegans, the roles of chromatin regulation in development have been explored in several contexts, including vulval differentiation. The synthetic multivulva (synMuv) genes are regulators of vulval development in C. elegans and the proteins encoded by these genes include components of several histone modification and chromatin remodelling complexes. By inhibiting ectopic expression of the epidermal growth factor (LIN-3) in the nematode hypodermis, the synMuv genes prevent inappropriate vulval induction. In a forward genetic screen for modifiers of the expression of a hypodermal reporter gene, we identified a mutation that results in increased expression of the reporter. This mutation also suppresses ectopic vulval induction in synMuv mutants and we have consequently named the affected gene suppressor of synthetic multivulva-1 (sumv-1). We show that SUMV-1 is required in the hypodermis for the synMuv phenotype and that loss of sumv-1 function suppresses ectopic expression of lin-3 in synMuv mutant animals. In yeast two-hybrid assays SUMV-1 physically interacts with SUMV-2, and reduction of sumv-2 function also suppresses the synMuv phenotype. We identified similarities between SUMV-1 and SUMV-2 and mammalian proteins KAT8 NSL2 and KAT8 NSL3, respectively, which are components of the KAT8/MOF histone acetyltransferase complex. Reduction of function of mys-2, which encodes the enzymatic component of the KAT8/MOF complex, also suppresses the synMuv phenotype, and MYS-2 physically interacts with SUMV-2 in yeast two-hybrid assays. Together these observations suggest that SUMV-1 and SUMV-2 may function together with MYS-2 in a nematode KAT8/MOF-like complex to antagonise the activity of the synMuv genes.

Hit and Run Transcriptional Repressors Are Difficult to Catch in the Act

Publisher: Wiley

Date: 27-06-2019

DOI: 10.1002/BIES.201900041

Abstract: Transcriptional silencing may not necessarily depend on the continuous residence of a sequence-specific repressor at a control element and may act via a "hit and run" mechanism. Due to limitations in assays that detect transcription factor (TF) binding, such as chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), this phenomenon may be challenging to detect and therefore its prevalence may be underappreciated. To explore this possibility, erythroid gene promoters that are regulated directly by GATA1 in an inducible system are analyzed. It is found that many regulated genes are bound immediately after induction of GATA1 but the residency of GATA1 decreases over time, particularly at repressed genes. Furthermore, it is shown that the repressive mark H3K27me3 is seldom associated with bound repressors, whereas, in contrast, the active (H3K4me3) histone mark is overwhelmingly associated with TF binding. It is hypothesized that during cellular differentiation and development, certain genes are silenced by repressive TFs that subsequently vacate the region. Catching such repressor TFs in the act of silencing via assays such as ChIP-seq is thus a temporally challenging prospect. The use of inducible systems, epitope tags, and alternative techniques may provide opportunities for detecting elusive "hit and run" transcriptional silencing. Also see the video abstract here youtu.be/vgrsoP_HF3g.

Mutations ofZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot

Publisher: Hindawi Limited

Date: 24-09-2003

DOI: 10.1002/HUMU.10261

Abstract: Two out of 47 patients with sporadic tetralogy of Fallot (TOF), the most common cyanotic conotruncal heart defect (CTD), showed heterozygous missense mutations of the ZFPM2/FOG2 gene. Knockout mice carrying mutations in the ZFPM2/FOG2 gene have similarly been found to exhibit TOF. While both mutant ZFPM2/FOG2 proteins, E30G (c.88A>G) and S657G (c.1968A>G), retain the ability to bind the partner protein GATA4 and repress GATA4 mediated gene activation, the S657G, but not the E30G, mutation is subtly impaired in this function. ZFPM2/FOG2 gene mutations may contribute to some sporadic cases of TOF.

Phosphorylation of Krüppel-like Factor 3 (KLF3/BKLF) and C-terminal Binding Protein 2 (CtBP2) by Homeodomain-interacting Protein Kinase 2 (HIPK2) Modulates KLF3 DNA Binding and Activity

Publisher: Elsevier BV

Date: 03-2015

DOI: 10.1074/JBC.M115.638338

Loss of Kruppel-Like Factor 3 (KLF3/BKLF) Leads to Upregulation of the Insulin-Sensitizing Factor Adipolin (FAM132A/CTRP12/C1qdc2)

Publisher: American Diabetes Association

Date: 17-07-2013

DOI: 10.2337/DB12-1745

Abstract: Krüppel-like factor 3 (KLF3) is a transcriptional regulator that we have shown to be involved in the regulation of adipogenesis in vitro. Here, we report that KLF3-null mice are lean and protected from diet-induced obesity and glucose intolerance. On a chow diet, plasma levels of leptin are decreased, and adiponectin is increased. Despite significant reductions in body weight and adiposity, wild-type and knockout animals show equivalent energy intake, expenditure, and excretion. To investigate the molecular events underlying these observations, we used microarray analysis to compare gene expression in Klf3+/+ and Klf3−/− tissues. We found that mRNA expression of Fam132a, which encodes a newly identified insulin-sensitizing adipokine, adipolin, is significantly upregulated in the absence of KLF3. We confirmed that KLF3 binds the Fam132a promoter in vitro and in vivo and that this leads to repression of promoter activity. Further, plasma adipolin levels were significantly increased in Klf3−/− mice compared with wild-type littermates. Boosting levels of adipolin via targeting of KLF3 offers a novel potential therapeutic strategy for the treatment of insulin resistance.

Protein interactions: is seeing believing?

Publisher: Elsevier BV

Date: 12-2007

DOI: 10.1016/J.TIBS.2007.09.006

Involvement of the N-finger in the self-association of GATA-1

Publisher: Elsevier BV

Date: 11-1998

DOI: 10.1074/JBC.273.46.30560

Krüppel-like factor 3 (KLF3/BKLF) is required for widespread repression of the inflammatory modulator galectin-3 (Lgals3)

Publisher: Elsevier BV

Date: 07-2016

DOI: 10.1074/JBC.M116.715748

The transactivation domain within cysteine/histidine-rich region 1 of CBP comprises two novel zinc-binding modules

Publisher: Elsevier BV

Date: 05-2000

DOI: 10.1074/JBC.M910396199

A novel corepressor, BCoR-L1, represses transcription through an interaction with CtBP.

Publisher: Elsevier BV

Date: 05-2007

DOI: 10.1074/JBC.M700246200

Transcription Factor Erythroid Krüppel-like Factor (ELKF) Is Essential for the Erythropoietin-induced Hemoglobin Production but Not for Proliferation, Viability, or Morphological Maturation

Publisher: Elsevier BV

Date: 09-1998

DOI: 10.1074/JBC.273.37.23793

The identification and structure of an N-terminal PR domain show that FOG1 is a member of the PRDM family of proteins

Publisher: Public Library of Science (PLoS)

Date: 27-08-2014

DOI: 10.1371/JOURNAL.PONE.0106011

A class of zinc fingers involved in protein-protein interactions

Publisher: Wiley

Date: 02-2000

DOI: 10.1046/J.1432-1327.2000.01095.X

Abstract: Zinc fingers (ZnFs) are extremely common protein domains. Several classes of ZnFs are distinguished by the nature and spacing of their zinc-coordinating residues. While the structure and function of some ZnFs are well characterized, many others have been identified only through their amino acid sequence. A number of proteins contain a conserved C-X2-C-X12-H-X1-5-C sequence, which is similar to the spacing observed for the 'classic' CCHH ZnFs. Although these domains have been implicated in protein-protein (and not protein-nucleic acid) interactions, nothing is known about their structure or function at a molecular level. Here, we address this problem through the expression and biophysical characterization of several CCHC-type zinc fingers from the erythroid transcription factor FOG and the related Drosophila protein U-shaped. Each of these domains does indeed fold in a zinc-dependent fashion, coordinating the metal in a tetrahedral manner through the sidechains of one histidine and three cysteine residues, and forming extremely thermostable structures. Analysis of CD spectra suggests an overall fold similar to that of the CCHH fingers, and indeed a point mutant of FOG-F1 in which the final cysteine residue is replaced by histidine remains capable of folding. However, the CCHC (as opposed to CCHH) motif is a prerequisite for GATA-1 binding activity, demonstrating that CCHC and CCHH topologies are not interchangeable. This demonstration that members of a structurally distinct subclass of genuine zinc finger domains are involved in the mediation of protein-protein interactions has implications for the prediction of protein function from nucleotide sequences.

Erratum to: Repression of chimeric transcripts emanating from endogenous retrotransposons by a sequence-specific transcription factor [Genome Biology, 15 (2014) R58]

Publisher: Springer Science and Business Media LLC

Date: 03-06-2016

DOI: 10.1186/S13059-016-0977-1

Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

Publisher: American Association for the Advancement of Science (AAAS)

Date: 15-01-2016

DOI: 10.1126/SCIENCE.AAD3312

Abstract: Mutation of adult-type globin genes causes sickle cell disease and thalassemia. Although treating these hemoglobinopathies with gene therapy is possible, there is a pressing need for pharmacologic approaches to treat general patient populations. One promising approach is to reactivate repressed expression of fetal-type hemoglobin (HbF) in adult erythroid cells. Masuda et al. reveal a molecular mechanism governing HbF repression as mediated by the LRF/ZBTB7A transcription factor. The study may encourage the development of new HbF reactivation therapies for hemoglobinopathies. Science , this issue p. 285

Repression of chimeric transcripts emanating from endogenous retrotransposons by a sequence-specific transcription factor

Publisher: Springer Science and Business Media LLC

Date: 04-2014

DOI: 10.1186/GB-2014-15-4-R58

Mechanisms Directing the Nuclear Localization of the CtBP Family Proteins

Publisher: Informa UK Limited

Date: 07-2006

DOI: 10.1128/MCB.02402-05

Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin

Publisher: Springer Science and Business Media LLC

Date: 14-05-2015

DOI: 10.1038/NCOMMS8085

Abstract: Genetic disorders resulting from defects in the adult globin genes are among the most common inherited diseases. Symptoms worsen from birth as fetal γ-globin expression is silenced. Genome editing could permit the introduction of beneficial single-nucleotide variants to ameliorate symptoms. Here, as proof of concept, we introduce the naturally occurring Hereditary Persistance of Fetal Haemoglobin (HPFH) -175T>C point mutation associated with elevated fetal γ-globin into erythroid cell lines. We show that this mutation increases fetal globin expression through de novo recruitment of the activator TAL1 to promote chromatin looping of distal enhancers to the modified γ-globin promoter.

Recovery from Hemophilia B Leyden: An Androgen-Responsive Element in the Factor IX Promoter

Publisher: American Association for the Advancement of Science (AAAS)

Date: 17-07-1992

DOI: 10.1126/SCIENCE.1631558

Abstract: One form of the inherited, X-linked, bleeding disorder, hemophilia B, resolves after puberty. Mutations at -20 and -26 in the clotting factor IX promoter impair transcription by disrupting the binding site for the liver-enriched transcription factor LF-A1/HNF4. The -26 but not the -20 mutation also disrupts an androgen-responsive element, which overlaps the LF-A1/HNF4 site. This explains the improvement seen in patients with the -20 mutation and the failure of the -26 patient to recover.

The Horizon Run 5 Cosmological Hydrodynamical Simulation: Probing Galaxy Formation from Kilo- to Gigaparsec Scales

Publisher: American Astronomical Society

Date: 08-02-2021

DOI: 10.3847/1538-4357/ABD08B

HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription.

Publisher: Springer Science and Business Media LLC

Date: 08-08-2022

DOI: 10.1038/S41588-022-01152-6

Abstract: The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (HBG) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of BCL11A transcription. HIC2 and BCL11A are reciprocally expressed during development. Forced expression of HIC2 in adult erythroid cells inhibits BCL11A transcription and induces HBG expression. HIC2 binds to erythroid BCL11A enhancers to reduce chromatin accessibility and binding of transcription factor GATA1, diminishing enhancer activity and enhancer-promoter contacts. DNA-binding and crystallography studies reveal direct steric hindrance as one mechanism by which HIC2 inhibits GATA1 binding at a critical BCL11A enhancer. Conversely, loss of HIC2 in fetal erythroblasts increases enhancer accessibility, GATA1 binding and BCL11A transcription. HIC2 emerges as an evolutionarily conserved regulator of hemoglobin switching via developmental control of BCL11A.

Structural basis for human ZBTB7A action at the fetal globin promoter

Publisher: Elsevier BV

Date: 09-2021

DOI: 10.1016/J.CELREP.2021.109759

A new zinc binding fold underlines the versatility of zinc binding modules in protein evolution

Publisher: Elsevier BV

Date: 05-2002

DOI: 10.1016/S0969-2126(02)00757-8

Abstract: Many different zinc binding modules have been identified. Their abundance and variety suggests that the formation of zinc binding folds might be relatively common. We have determined the structure of CH1(1), a 27-residue peptide derived from the first cysteine/histidine-rich region (CH1) of CREB binding protein (CBP). This peptide forms a highly ordered zinc-dependent fold that is distinct from known folds. The structure differs from a subsequently determined structure of a larger region from the CH3 region of CBP, and the CH1(1) fold probably represents a nonphysiologically active form. Despite this, the fold is thermostable and tolerant to both multiple alanine mutations and changes in the zinc-ligand spacing. Our data support the idea that zinc binding domains may arise frequently. Additionally, such structures may prove useful as scaffolds for protein design, given their stability and robustness.

The LIM Protein FHL3 Binds Basic Krüppel-like Factor/Krüppel-like Factor 3 and Its Co-repressor C-terminal-binding Protein 2

Publisher: Elsevier BV

Date: 04-2003

DOI: 10.1074/JBC.M300587200

KLF1 drives the expression of fetal hemoglobin in British HPFH

Publisher: American Society of Hematology

Date: 10-08-2017

DOI: 10.1182/BLOOD-2017-02-767400

Abstract: Introduction of the British HPFH mutation into the fetal globin promoter in a human cell model causes elevated fetal globin expression. The British HPFH mutation creates a de novo binding site both in vitro and in vivo for the potent erythroid activator KLF1.

Formation and Morphology of the First Galaxies in the Cosmic Morning

Publisher: American Astronomical Society

Date: 09-2022

DOI: 10.3847/1538-4357/AC85B5

Abstract: We investigate the formation and morphological evolution of the first galaxies in the cosmic morning (10 ≳ z ≳ 4) using the Horizon Run 5 ( HR5 ) simulation. For galaxies above the stellar mass M ⋆ , min = 2 × 10 9 M ⊙ , we classify them into disk, spheroid, and irregular types according to their asymmetry and stellar-mass morphology. We find that about two-thirds of the galaxies have a Sérsic index .5, reflecting the dominance of disk-type morphology in the cosmic morning. The rest are evenly distributed as incidental and transient irregulars or spheroids. These fractions are roughly independent of redshift and stellar mass up to ∼10 10 M ⊙ . Almost all the first galaxies with M ⋆ M ⋆ , min at z 4 form at initial peaks of the matter-density field. Large-scale structures in the universe emerge and grow like cosmic rhizomes as the underlying matter-density fluctuations grow and form associations of galaxies in rare overdense regions and the realm of the galactic world is stretched into relatively lower-density regions along evolving filaments. The cosmic web of galaxies forms at lower redshifts when most rhizomes globally percolate. The primordial angular momentum produced by the induced tidal torques on protogalactic regions is correlated with the internal kinematics of galaxies and tightly aligned with the angular momentum of the total galaxy mass. The large-scale tidal field imprinted in the initial conditions seems responsible for the dominance of disk morphology and for the tendency of galaxies to reacquire a disk postdistortion.

Structural basis of simultaneous recruitment of the transcriptional regulators LMO2 and FOG1/ZFPM1 by the transcription factor GATA1

Publisher: Proceedings of the National Academy of Sciences

Date: 15-08-2011

DOI: 10.1073/PNAS.1105898108

Abstract: The control of red blood cell and megakaryocyte development by the regulatory protein GATA1 is a paradigm for transcriptional regulation of gene expression in cell lineage differentiation and maturation. Most GATA1-regulated events require GATA1 to bind FOG1, and essentially all GATA1-activated genes are cooccupied by a TAL1/E2A/LMO2/LDB1 complex however, it is not known whether FOG1 and TAL1/E2A/LMO2/LDB1 are simultaneously recruited by GATA1. Our structural data reveal that the FOG1-binding domain of GATA1, the N finger, can also directly contact LMO2 and show that, despite the small size ( 50 residues) of the GATA1 N finger, both FOG1 and LMO2 can simultaneously bind this domain. LMO2 in turn can simultaneously contact both GATA1 and the DNA-binding protein TAL1/E2A at bipartite E-box/WGATAR sites. Taken together, our data provide the first structural snapshot of multiprotein complex formation at GATA1-dependent genes and support a model in which FOG1 and TAL1/E2A/LMO2/LDB1 can cooccupy E-box/WGATAR sites to facilitate GATA1-mediated activation of gene activation.

The regulation of human globin promoters by CCAAT box elements and the recruitment of NF-Y

Publisher: Elsevier BV

Date: 05-2017

DOI: 10.1016/J.BBAGRM.2016.10.002

Abstract: CCAAT boxes are motifs found within the proximal promoter of many genes, including the human globin genes. The highly conserved nature of CCAAT box motifs within the promoter region of both α-like and β-like globin genes emphasises the functional importance of the CCAAT sequence in globin gene regulation. Mutations within the β-globin CCAAT box result in β-thalassaemia, while mutations within the distal γ-globin CCAAT box cause the Hereditary Persistence of Foetal Haemoglobin, a benign condition which results in continued γ-globin expression during adult life. Understanding the transcriptional regulation of the globin genes is of particular interest, as reactivating the foetal γ-globin gene alleviates the symptoms of β-thalassaemia and sickle cell anaemia. NF-Y is considered to be the primary activating transcription factor which binds to globin CCAAT box motifs. Here we review recruitment of NF-Y to globin CCAAT boxes and the role NF-Y plays in regulating globin gene expression. This article is part of a Special Issue entitled: Nuclear Factor Y in Development and Disease, edited by Prof. Roberto Mantovani.

Key challenges in bringing CRISPR-mediated somatic cell therapy into the clinic

Publisher: Springer Science and Business Media LLC

Date: 25-09-2017

DOI: 10.1186/S13073-017-0475-4

Genome Editing of Erythroid Cell Culture Model Systems

Publisher: Springer New York

Date: 27-10-2017

DOI: 10.1007/978-1-4939-7428-3_15

Abstract: Genome editing to introduce specific mutations or to knock out genes in model cell systems has become an efficient platform for research in the fields of molecular biology, genetics, and cell biology. With recent rapid improvements in genome editing techniques, bench-top manipulation of the genome in cell culture has become progressively easier. The application of this knowledge to erythroid cell culture systems now allows the rapid analysis of the downstream effects of virtually any engineered gene disruption or modification in cell systems. Here, we describe a CRISPR/Cas9-based approach to making genomic modifications in erythroid lineage cells which we have successfully used in both murine (MEL) and human (K562) erythroleukaemia immortalized cell lines.

The Role of the Coiled-Coil Motif in Interactions Mediated by TPD52

Publisher: Elsevier BV

Date: 10-2001

DOI: 10.1006/BBRC.2001.5721

Amplification of zinc finger gene 217 (ZNF217) and cancer: When good fingers go bad

Publisher: Elsevier BV

Date: 06-2007

DOI: 10.1016/J.BBCAN.2007.05.001

Abstract: Chromosome 20q13 is highly lified in human cancers, including 20-30% of early stage human breast cancers. The lification correlates with poor prognosis. Over-expression of the zinc-finger protein 217 (ZNF217), a candidate oncogene on 20q13.2, in cultured human mammary and ovarian epithelial cells can lead to their immortalization, indicating that selection for ZNF217 expression may drive 20q13 lification during critical early stages of cancer progression. ZNF217 can also attenuate apoptotic signals resulting from exposure to doxorubicin, suggesting that ZNF217 expression may also be involved in resistance to chemotherapy. Recent findings indicate that ZNF217 binds specific DNA sequences, recruits the co-repressor C-terminal binding protein (CtBP), and represses the transcription of a variety of genes. Inappropriate expression of ZNF217 may lead to aberrant down-regulation of genes involved in limiting the proliferation, survival, and/or invasiveness of cancer cells. Better understanding of ZNF217 and its associated pathways may provide new targets for therapeutic intervention in human cancers.

Basic Krüppel-like factor functions within a network of interacting haematopoietic transcription factors

Publisher: Elsevier BV

Date: 10-1999

DOI: 10.1016/S1357-2725(99)00067-9

Abstract: Basic Krüppel-like Factor (BKLF) is a recently recognized member of a small group of transcription factors that bind CACCC motifs in DNA, by means of three highly conserved C-terminal Krüppel-like (typically Cys-X2-4-Cys-X12-His-X3-4-His) zinc fingers. Together with Erythroid Krüppel-like Factor (EKLF), it is one of the most abundant CACCC-binding proteins in erythroid cells. In contrast to EKLF, BKLF can act to repress transcription and thus may serve to moderate EKLF activity in vivo. Interestingly, it has also been shown that BKLF expression in erythroid cells is dependent on EKLF. Analysis of proteins interacting with BKLF indicates that it represses transcription by recruiting the general co-repressor protein CtBP, a cofactor that also associates with other haematopoietic transcriptional repressors such as Evi-1 and ZEB/AREB6. The observation that mice deficient in BKLF exhibit a myeloproliferative disorder suggests that BKLF regulates important processes involved in haematopoietic differentiation.

Disrupting the adult globin promoter alleviates promoter competition and reactivates fetal globin gene expression

Publisher: American Society of Hematology

Date: 07-04-2022

DOI: 10.1182/BLOOD.2021014205

Abstract: The benign condition hereditary persistence of fetal hemoglobin (HPFH) is known to ameliorate symptoms of co-inherited β-hemoglobinopathies, such as sickle cell disease and β-thalassemia. The condition is sometimes associated with point mutations in the fetal globin promoters that disrupt the binding of the repressors BCL11A or ZBTB7A/LRF, which have been extensively studied. HPFH is also associated with a range of deletions within the β-globin locus that all reside downstream of the fetal HBG2 gene. These deletional forms of HPFH are poorly understood and are the focus of this study. Numerous different mechanisms have been proposed to explain how downstream deletions can boost the expression of the fetal globin genes, including the deletion of silencer elements, of genes encoding noncoding RNA, and bringing downstream enhancer elements into proximity with the fetal globin gene promoters. Here we systematically analyze the deletions associated with both HPFH and a related condition known as δβ-thalassemia and propose a unifying mechanism. In all cases where fetal globin is upregulated, the proximal adult β-globin (HBB) promoter is deleted. We use clustered regularly interspaced short palindromic repeats-mediated gene editing to delete or disrupt elements within the promoter and find that virtually all mutations that reduce ΗΒΒ promoter activity result in elevated fetal globin expression. These results fit with previous models where the fetal and adult globin genes compete for the distal locus control region and suggest that targeting the ΗΒΒ promoter might be explored to elevate fetal globin and reduce sickle globin expression as a treatment of β-hemoglobinopathies.

The N-terminal Zinc Finger of the Erythroid Transcription Factor GATA-1 Binds GATC Motifs in DNA

Publisher: Elsevier BV

Date: 09-2001

DOI: 10.1074/JBC.M106256200

Methylation of a CGATA element inhibits binding and regulation by GATA-1

Publisher: Springer Science and Business Media LLC

Date: 22-05-2020

DOI: 10.1038/S41467-020-16388-1

Abstract: Alterations in DNA methylation occur during development, but the mechanisms by which they influence gene expression remain uncertain. There are few ex les where modification of a single CpG dinucleotide directly affects transcription factor binding and regulation of a target gene in vivo. Here, we show that the erythroid transcription factor GATA-1 — that typically binds T/AGATA sites — can also recognise CGATA elements, but only if the CpG dinucleotide is unmethylated. We focus on a single CGATA site in the c-Kit gene which progressively becomes unmethylated during haematopoiesis. We observe that methylation attenuates GATA-1 binding and gene regulation in cell lines. In mice, converting the CGATA element to a TGATA site that cannot be methylated leads to accumulation of megakaryocyte-erythroid progenitors. Thus, the CpG dinucleotide is essential for normal erythropoiesis and this study illustrates how a single methylated CpG can directly affect transcription factor binding and cellular regulation.

Solution structure of the THAP domain from Caenorhabditis elegans C-terminal binding protein (CtBP).

Publisher: Elsevier BV

Date: 02-2006

DOI: 10.1016/J.JMB.2006.11.058

Abstract: The THAP (Thanatos-associated protein) domain is a recently discovered zinc-binding domain found in proteins involved in transcriptional regulation, cell-cycle control, apoptosis and chromatin modification. It contains a single zinc atom ligated by cysteine and histidine residues within a Cys-X(2-4)-Cys-X(35-53)-Cys-X(2)-His consensus. We have determined the NMR solution structure of the THAP domain from Caenorhabditis elegans C-terminal binding protein (CtBP) and show that it adopts a fold containing a treble clef motif, bearing similarity to the zinc finger-associated domain (ZAD) from Drosophila Grauzone. The CtBP THAP domain contains a large, positively charged surface patch and we demonstrate that this domain can bind to double-stranded DNA in an electrophoretic mobility-shift assay. These data, together with existing reports, indicate that THAP domains might exhibit a functional ersity similar to that observed for classical and GATA-type zinc fingers.

Evi-1 Transforming and Repressor Activities Are Mediated by CtBP Co-repressor Proteins

Publisher: Elsevier BV

Date: 07-2001

DOI: 10.1074/JBC.M102343200

FOG, a Multitype Zinc Finger Protein, Acts as a Cofactor for Transcription Factor GATA-1 in Erythroid and Megakaryocytic Differentiation

Publisher: Elsevier BV

Date: 07-1997

DOI: 10.1016/S0092-8674(00)80318-9

Abstract: The hematopoietic transcription factor GATA-1 is essential for development of the erythroid and megakaryocytic lineages. Using the conserved zinc finger DNA-binding domain of GATA-1 in the yeast two-hybrid system, we have identified a novel, multitype zinc finger protein, Friend of GATA-1 (FOG), which binds GATA-1 but not a functionally inactive mutant lacking the amino (N) finger. FOG is coexpressed with GATA-1 during embryonic development and in erythroid and megakaryocytic cells. Furthermore, FOG and GATA-1 synergistically activate transcription from a hematopoietic-specific regulatory region and cooperate during both erythroid and megakaryocytic cell differentiation. These findings indicate that FOG acts as a cofactor for GATA-1 and provide a paradigm for the regulation of cell type-specific gene expression by GATA transcription factors.

Zinc fingers as protein recognition motifs: Structural basis for the GATA-1/friend of GATA interaction

Publisher: Proceedings of the National Academy of Sciences

Date: 11-01-2005

DOI: 10.1073/PNAS.0407511102

Abstract: GATA-1 and friend of GATA (FOG) are zinc-finger transcription factors that physically interact to play essential roles in erythroid and megakaryocytic development. Several naturally occurring mutations in the GATA-1 gene that alter the FOG-binding domain have been reported. The mutations are associated with familial anemias and thrombocytopenias of differing severity. To elucidate the molecular basis for the GATA-1/FOG interaction, we have determined the three-dimensional structure of a complex comprising the interaction domains of these proteins. The structure reveals how zinc fingers can act as protein recognition motifs. Details of the architecture of the contact domains and their physical properties provide a molecular explanation for how the GATA-1 mutations contribute to distinct but related genetic diseases.

Role of the C-Terminal Binding Protein PXDLS Motif Binding Cleft in Protein Interactions and Transcriptional Repression

Publisher: Informa UK Limited

Date: 11-2006

DOI: 10.1128/MCB.00445-06

CCHX zinc finger derivatives retain the ability to bind Zn(II) and mediate protein-DNA interactions

Publisher: Elsevier BV

Date: 07-2003

DOI: 10.1074/JBC.M211146200

Identification of regulatory regions within the KAI1 promoter: a role for binding of AP1, AP2 and p53

Publisher: Elsevier BV

Date: 2003

DOI: 10.1016/S0378-1119(02)01101-0

Abstract: The mechanism underlying loss of KAI1 gene expression in invasive and metastatic tumour cells is unknown. A possible scenario could involve altered expression or function of protein factors normally involved in regulating KAI1 transcription. To explore this possibility, we have initiated a study to characterise regulatory elements of the KAI1 promoter, using as a model, two bladder cancer cell lines (BL13 and HT1376) expressing high levels of endogenous KAI1 messenger RNA (mRNA). Transfection experiments using reporter plasmids with progressive KAI1 promoter deletions, identified a 76 bp region upstream of the transcription initiation site which contained putative binding motifs for AP2, p53 and AP1, as essential for reporter activity. DNA-binding studies using nuclear extracts from both cell lines, showed that AP1 and AP2 formed specific complexes with oligonucleotides containing KAI1 promoter motifs. Mutation of either motif abrogated reporter activity and abolished specific complex formation. In BL13 cells (endogenous wildtype p53), but not in HT1376 cells (endogenous mutant p53), mutation of the p53-binding motif also abrogated reporter activity and abolished specific complex formation in gel shift assays. These data suggested that a combination of AP2, p53 and AP1 binding to specific motifs within the KAI1 promoter might be required for high level promoter activity and that loss of expression or function of these factors might contribute to loss of KAI1 expression in invasive tumours and tumour cell lines. To explore this possibility, we examined levels of these proteins in nuclear extracts of BL13 and HT1376, as well as three bladder cancer cell lines which expressed little or no KAI1 mRNA. Our data suggested that a loss of KAI1 mRNA was not simply due to absence of AP2, AP1 or p53 expression.

Protein-Protein Interaction between Fli-1 and GATA-1 Mediates Synergistic Expression of Megakaryocyte-Specific Genes through Cooperative DNA Binding

Publisher: Informa UK Limited

Date: 06-2004

DOI: 10.1128/MCB.24.11.5088.2004

GATA Proteins Work Together with Friend of GATA (FOG) and C-terminal Binding Protein (CTBP) Co-regulators to Control Adipogenesis

Publisher: Elsevier BV

Date: 10-2010

DOI: 10.1074/JBC.M110.141317

Solution structures of two CCHC zinc fingers from the FOG family protein U-shaped that mediate protein-protein interactions

Publisher: Elsevier BV

Date: 11-2000

DOI: 10.1016/S0969-2126(00)00527-X

Abstract: Zinc finger domains have traditionally been regarded as sequence-specific DNA binding motifs. However, recent evidence indicates that many zinc fingers mediate specific protein-protein interactions. For instance, several zinc fingers from FOG family proteins have been shown to interact with the N-terminal zinc finger of GATA-1. We have used NMR spectroscopy to determine the first structures of two FOG family zinc fingers that are involved in protein-protein interactions: fingers 1 and 9 from U-shaped. These fingers resemble classical TFIIIA-like zinc fingers, with the exception of an unusual extended portion of the polypeptide backbone prior to the fourth zinc ligand. [15N,(1)H]-HSQC titrations have been used to define the GATA binding surface of USH-F1, and comparison with other FOG family proteins indicates that the recognition mechanism is conserved across species. The surface of FOG-type fingers that interacts with GATA-1 overlaps substantially with the surface through which classical fingers typically recognize DNA. This suggests that these fingers could not contact both GATA and DNA simultaneously. In addition, results from NMR, gel filtration, and sedimentation equilibrium experiments suggest that the interactions are of moderate affinity. Our results demonstrate unequivocally that zinc fingers comprising the classical betabetaalpha fold are capable of mediating specific contacts between proteins. The existence of this alternative function has implications for the prediction of protein function from sequence data and for the evolution of protein function.

C-terminal binding protein: A metabolic sensor implicated in regulating adipogenesis

Publisher: Elsevier BV

Date: 05-2011

DOI: 10.1016/J.BIOCEL.2011.01.017

Abstract: The development of mature adipocytes from preadipocyte precursor cells requires coordinated changes in gene expression. Management of these expression changes relies on the actions of both DNA-binding transcription factors and their coregulators. Recent studies have identified the corepressor C-terminal binding protein (CtBP) as a key transcriptional coregulator in adipose tissue. CtBP proteins work with several different partner proteins to regulate the development of both white and brown adipocytes. CtBP is of particular interest as it binds to NAD(+)/NADH and may respond to the metabolic state of the cell, thereby linking changes in nutrient levels to transcriptional outcomes.

Molecular analysis of the interaction between the hematopoietic master transcription factors GATA-1 and PU

Publisher: Elsevier BV

Date: 09-2006

DOI: 10.1074/JBC.M602830200

Role for SUMO Modification in Facilitating Transcriptional Repression by BKLF

Publisher: Informa UK Limited

Date: 02-2005

DOI: 10.1128/MCB.25.4.1549-1559.2005

Sticky fingers: zinc-fingers as protein-recognition motifs

Publisher: Elsevier BV

Date: 02-2007

DOI: 10.1016/J.TIBS.2006.12.007

Abstract: Zinc-fingers (ZnFs) are extremely abundant in higher eukaryotes. Once considered to function exclusively as sequence-specific DNA-binding motifs, ZnFs are now known to have additional activities such as the recognition of RNA and other proteins. Here we discuss recent advances in our understanding of ZnFs as specific modules for protein recognition. Structural studies of ZnF complexes reveal considerable ersity in terms of protein partners, binding modes and affinities, and highlight the often underestimated versatility of ZnF structure and function. An appreciation of the structural features of ZnF-protein interactions will contribute to our ability to engineer and to use ZnFs with tailored protein-binding properties.

Is there a telltale RH fingerprint in zinc fingers that recognizes methylated CpG dinucleotides?

Publisher: Elsevier BV

Date: 09-2013

DOI: 10.1016/J.TIBS.2013.06.005

Boosting Capacitive Sodium-Ion Storage in Electrochemically Exfoliated Graphite for Sodium-Ion Capacitors

Publisher: American Chemical Society (ACS)

Date: 13-11-2020

DOI: 10.1021/ACSAMI.0C14611

Potent and uniform fetal hemoglobin induction via base editing

Publisher: Springer Science and Business Media LLC

Date: 07-2023

DOI: 10.1038/S41588-023-01434-7

hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation.

Publisher: Elsevier BV

Date: 08-1999

DOI: 10.1074/JBC.274.33.23491

Krüppel-like factor 3 (KLF3) suppresses NF-kB-driven inflammation in mice.

Publisher: Elsevier BV

Date: 05-2020

DOI: 10.1074/JBC.RA120.013114

Engineering a protein scaffold from a PHD finger

Publisher: Elsevier BV

Date: 07-2003

DOI: 10.1016/S0969-2126(03)00122-9

Abstract: The design of proteins with tailored functions remains a relatively elusive goal. Small size, a well-defined structure, and the ability to maintain structural integrity despite multiple mutations are all desirable properties for such designer proteins. Many zinc binding domains fit this description. We determined the structure of a PHD finger from the transcriptional cofactor Mi2beta and investigated the suitability of this domain as a scaffold for presenting selected binding functions. The two flexible loops in the structure were mutated extensively by either substitution or expansion, without affecting the overall fold of the domain. A binding site for the corepressor CtBP2 was also grafted onto the domain, creating a new PHD domain that can specifically bind CtBP2 both in vitro and in the context of a eukaryotic cell nucleus. These results represent a step toward designing new regulatory proteins for modulating aberrant gene expression in vivo.

Hls5 regulated erythroid differentiation by modulating GATA-1 activity

Publisher: American Society of Hematology

Date: 15-02-2008

DOI: 10.1182/BLOOD-2007-04-085746

Abstract: Hemopoietic lineage switch (Hls) 5 and 7 were originally isolated as genes up-regulated during an erythroid-to-myeloid lineage switch. We have shown previously that Hls7/Mlf1 imposes a monoblastoid phenotype on erythroleukemic cells. Here we show that Hls5 impedes erythroid maturation by restricting proliferation and inhibiting hemoglobin synthesis however, Hls5 does not influence the morphology of erythroid cells. Under the influence of GATA-1, Hls5 relocates from cytoplasmic granules to the nucleus where it associates with both FOG-1 and GATA-1. In the nucleus, Hls5 is able to suppress GATA-1–mediated transactivation and reduce GATA-1 binding to DNA. We conclude that Hls5 and Hls7/Mlf1 act cooperatively to induce biochemical and phenotypic changes associated with erythroid/myeloid lineage switching.

A less severe form of Haemophilia B Leyden

Publisher: Oxford University Press (OUP)

Date: 11-08-1990

DOI: 10.1093/NAR/18.15.4633

The transcriptional repressor CTBP-1 functions in the nervous system of Caenorhabditis elegans to regulate lifespan.

Publisher: Elsevier BV

Date: 12-2014

DOI: 10.1016/J.EXGER.2014.09.022

Abstract: C-terminal binding proteins (CtBPs) are recruited by a variety of transcription factors to mediate gene repression. Nematode CTBP-1 has previously been shown to play a role in the regulation of lifespan Caenorhabditis elegans strains carrying a deletion in the ctbp-1 gene showed a 10-20% increase in mean and maximal lifespan compared with wild-type control strains. We set out to identify the tissues in which CTBP-1 functions to regulate lifespan in C. elegans. Our analysis of reporter genes shows that CTBP-1 is predominantly expressed in the nervous system with lower levels detectable in the hypodermis. Tissue-specific rescue experiments demonstrated that CTBP-1 functions in the nervous system to regulate lifespan. Previously, the lifespan extension in a ctbp-1 mutant was attributed, at least in part, to the misregulation of a lipase gene, lips-7. We therefore focussed on lips-7 and found that expressing CTBP-1 solely in the nervous system of a ctbp-1 mutant significantly reduced lips-7 transcription. In addition, we studied another ctbp-1 mutant allele that also displayed a long-lived phenotype. In this case, lips-7 expression was unaffected. This observation argues that, while lips-7 may play a role in lifespan, its de-repression is not essential for the extension of lifespan phenotype. We show that a prominent site of LIPS-7 expression is the hypodermis, one of the sites of fat storage in C. elegans. Interestingly, we did not observe co-localisation of CTBP-1 and lips-7 transcription in the nervous system, indicating that CTBP-1 may be acting indirectly, in a cell non-autonomous manner. In summary, our data confirm that CTBP-1 is involved in the regulation of lips-7 transcription but suggest that it may perform additional roles in the nervous system that contribute to the regulation of longevity.

Effective therapies for sickle cell disease: are we there yet?

Publisher: Elsevier BV

Date: 12-2022

DOI: 10.1016/J.TIG.2022.07.003

Abstract: Sickle cell disease (SCD) is a common genetic blood disorder associated with acute and chronic pain, progressive multiorgan damage, and early mortality. Recent advances in technologies to manipulate the human genome, a century of research and the development of techniques enabling the isolation, efficient genetic modification, and reimplantation of autologous patient hematopoietic stem cells (HSCs), mean that curing most patients with SCD could soon be a reality in wealthy countries. In parallel, ongoing research is pursuing more facile treatments, such as in-vivo-delivered genetic therapies and new drugs that can eventually be administered in low- and middle-income countries where most SCD patients reside.

Author Correction: HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription

Publisher: Springer Science and Business Media LLC

Date: 31-07-2023

DOI: 10.1038/S41588-023-01488-7

Generation of Mice Deficient in both KLF3/BKLF and KLF8 Reveals a Genetic Interaction and a Role for These Factors in Embryonic Globin Gene Silencing

Publisher: Informa UK Limited

Date: 08-2013

DOI: 10.1128/MCB.00074-13

A mechanism for Ikaros regulation of human globin gene switching

Publisher: Wiley

Date: 09-04-2008

DOI: 10.1111/J.1365-2141.2008.07065.X

Abstract: The human beta globin locus consists of an upstream LCR and functional genes arranged sequentially in the order of their expression during development: 5'-HBE1, HBG2, HBG1, HBD, HBB-3'. Haemoglobin switching entails the successive recruitment of these genes into an active chromatin hub (ACH). Here we show that the transcription factor Ikaros plays a major role in the formation of the beta-globin ACH, and in haemoglobin switching. In Plastic mice, where the DNA-binding region of Ikaros is disrupted by a point mutation, there is concomitant marked down-regulation of HBB, and up-regulation of HBG expression. We show for the first time Ikaros and its family member Eos, bind to critical cis elements implicated in haemoglobin switching and deletional hereditary persistence of fetal haemoglobin (HPFH). Chromatin conformation capture (3C) data demonstrated that Ikaros facilitates long-distance DNA looping between the LCR and a region upstream of HBD. This study provides new insights into the mechanism of stage-specific assembly of the beta-globin ACH, and HPFH.

The CtBP family: enigmatic and enzymatic transcriptional co-repressors

Publisher: Wiley

Date: 08-2001

DOI: 10.1002/BIES.1097

Abstract: Transcription factors that associate with DNA sequences in promoters and enhancers often recruit co-regulators that modulate their activity. Many of these co-regulators have intrinsic enzymatic activity and influence gene expression by modifying chromatin and altering its structure. Recently, a new family of co-repressors, the C-terminal binding proteins, has been described. These proteins recognize Pro-X-Asp-Leu-Ser (PXDLS) motifs in DNA-binding proteins and function as transcriptional co-repressors in Drosophila, Xenopus and mammals. The precise mechanisms by which they influence transcription are still under investigation. CtBP proteins dimerize and can contact histone deacetylases hence they may operate by linking deacetylases to DNA-bound factors. But it appears that CtBP proteins also have intrinsic enzymatic activity. They have significant homology to D-isomer-specific 2-hydroxy acid dehydrogenases, and remarkably one family member, rat CtBP, has been shown to have a second role, functioning as an acyl transferase in Golgi maintenance. These observations raise the possibility that CtBP proteins might regulate gene expression directly by means of their enzymatic activities, in addition to serving as simple bridging proteins. Supplementary material for this article can be found on the BioEssays homepage at pages/0265-9247/suppmat/v23_8.684.

Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers.

Publisher: Wiley

Date: 11-02-1970

DOI: 10.1093/EMBOJ/18.10.2812

Specific Recognition of ZNF217 and Other Zinc Finger Proteins at a Surface Groove of C-Terminal Binding Proteins

Publisher: Informa UK Limited

Date: 11-2006

DOI: 10.1128/MCB.00680-06

Activation and Repression of Interleukin-12 p40 Transcription by Erythroid Kruppel-like Factor in Macrophages

Publisher: Elsevier BV

Date: 04-2004

DOI: 10.1074/JBC.M400320200

Induction of AP-2α Expression by Adenoviral Infection Involves Inactivation of the AP-2rep Transcriptional Corepressor CtBP1

Publisher: Elsevier BV

Date: 07-2001

DOI: 10.1074/JBC.M100070200

Differential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cells

Publisher: Springer Science and Business Media LLC

Date: 16-05-2014

DOI: 10.1186/1471-2199-15-8

Cloning and characterization of mCtBP2, a co-repressor that associates with basic Kruppel-like factor and other mammalian transcriptional regulators

Publisher: Wiley

Date: 09-1998

DOI: 10.1093/EMBOJ/17.17.5129

Korea Institute For Advanced Study

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University Of Oxford

Location: United Kingdom of Great Britain and Northern Ireland

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University Of New South Wales

Location: Australia

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University Of Sydney

Location: Australia

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University Of Melbourne

Location: Australia

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Harvard University

Location: United States of America

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Discovery Projects - Grant ID: DP120103798

Start Date: 2012

End Date: 12-2015

Amount: $458,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0986928

Start Date: 03-2009

End Date: 03-2012

Amount: $290,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0984682

Start Date: 02-2009

End Date: 02-2012

Amount: $670,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP150103503

Start Date: 2015

End Date: 12-2017

Amount: $428,100.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0664941

Start Date: 02-2006

End Date: 12-2008

Amount: $530,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0342760

Start Date: 2003

End Date: 12-2005

Amount: $579,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP220101489

Start Date: 2022

End Date: 12-2024

Amount: $530,579.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP210200125

Start Date: 2023

End Date: 12-2025

Amount: $412,919.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP170101786

Start Date: 2017

End Date: 12-2019

Amount: $428,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100130

Start Date: 09-2010

End Date: 11-2011

Amount: $850,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100091

Start Date: 01-2012

End Date: 12-2014

Amount: $250,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100149

Start Date: 12-2014

End Date: 06-2015

Amount: $300,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0668241

Start Date: 2006

End Date: 12-2006

Amount: $824,610.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP180103785

Start Date: 2018

End Date: 12-2020

Amount: $598,198.00

Funder: Australian Research Council