ORCID Profile
0000-0002-5270-4347
Current Organisations
Friedrich Miescher Institute for Biomedical Research
,
South Australian immunoGENomics Cancer Institute
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Publisher: Springer Science and Business Media LLC
Date: 2023
Publisher: Cold Spring Harbor Laboratory
Date: 23-08-2022
DOI: 10.1101/2022.08.23.504916
Abstract: The genomic binding sites of the transcription factor (TF) and tumour suppressor p53 are unusually erse in regards to their chromatin features, including histone modifications, opening the possibility that chromatin provides context-dependence for p53 regulation. Here, we show that the ability of p53 to open chromatin and activate its target genes is indeed locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated lysine 4 of histone H3, thereby preferentially locating to those p53 sites that reside in closed chromatin, while it is deterred from accessible chromatin by lysine 4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to impact gene expression as a function of the local chromatin state. These findings link histone methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors which locally modulate TF function.
Publisher: Cold Spring Harbor Laboratory
Date: 02-2019
Publisher: Springer Science and Business Media LLC
Date: 26-03-2015
Publisher: eLife Sciences Publications, Ltd
Date: 06-07-2016
Publisher: Springer Science and Business Media LLC
Date: 12-07-2022
DOI: 10.1038/S41576-022-00512-6
Abstract: Cell type-specific gene expression relies on transcription factors (TFs) binding DNA sequence motifs embedded in chromatin. Understanding how motifs are accessed in chromatin is crucial to comprehend differential transcriptional responses and the phenotypic impact of sequence variation. Chromatin obstacles to TF binding range from DNA methylation to restriction of DNA access by nucleosomes depending on their position, composition and modification. In vivo and in vitro approaches now enable the study of TF binding in chromatin at unprecedented resolution. Emerging insights suggest that TFs vary in their ability to navigate chromatin states. However, it remains challenging to link binding and transcriptional outcomes to molecular characteristics of TFs or the local chromatin substrate. Here, we discuss our current understanding of how TFs access DNA in chromatin and novel techniques and directions towards a better understanding of this critical step in genome regulation.
Publisher: Oxford University Press (OUP)
Date: 07-04-2015
DOI: 10.1093/IJE/DYV024
Publisher: Springer Science and Business Media LLC
Date: 05-07-2023
DOI: 10.1038/S41586-023-06282-3
Abstract: The basic helix–loop–helix (bHLH) family of transcription factors recognizes DNA motifs known as E-boxes (CANNTG) and includes 108 members 1 . Here we investigate how chromatinized E-boxes are engaged by two structurally erse bHLH proteins: the proto-oncogene MYC-MAX and the circadian transcription factor CLOCK-BMAL1 (refs. 2,3 ). Both transcription factors bind to E-boxes preferentially near the nucleosomal entry–exit sites. Structural studies with engineered or native nucleosome sequences show that MYC-MAX or CLOCK-BMAL1 triggers the release of DNA from histones to gain access. Atop the H2A–H2B acidic patch 4 , the CLOCK-BMAL1 Per-Arnt-Sim (PAS) dimerization domains engage the histone octamer disc. Binding of tandem E-boxes 5–7 at endogenous DNA sequences occurs through direct interactions between two CLOCK-BMAL1 protomers and histones and is important for circadian cycling. At internal E-boxes, the MYC-MAX leucine zipper can also interact with histones H2B and H3, and its binding is indirectly enhanced by OCT4 elsewhere on the nucleosome. The nucleosomal E-box position and the type of bHLH dimerization domain jointly determine the histone contact, the affinity and the degree of competition and cooperativity with other nucleosome-bound factors.
Publisher: Cold Spring Harbor Laboratory
Date: 28-06-2021
DOI: 10.1101/2021.06.28.449463
Abstract: ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by a range of neurodevelopmental defects including Autism. Though it is highly conserved in vertebrates and essential for embryonic development the molecular functions of ZNF462 are unclear. We identified its murine homolog ZFP462 in a screen for epigenetic gene silencing in mouse embryonic stem cells (mESCs). Here, we show ZFP462 safeguards neural lineage specification by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to mediate epigenetic silencing of endodermal genes. ZFP462 binds to thousands of transposable elements (TEs) that harbor ESC- and endoderm-specific transcription factor (TF) binding sites and act as enhancers. Through physical interaction with G9A/GLP, ZFP462 seeds heterochromatin at TE-derived enhancers restricting the binding of core pluripotency TFs OCT4 and SOX2. Loss of ZFP462 in ESCs results in increased chromatin accessibility at target sites and ectopic expression of endodermal genes. Taken together, ZFP462 restricts TF binding and subsequent endodermspecific gene activation by conferring lineage and locus-specificity to the broadly expressed epigenetic regulator G9A/GLP. Our results suggest that aberrant activation of endodermal genes in the neuronal lineage underlies ZNF462-associated neurodevelopmental pathology.
Publisher: Springer Science and Business Media LLC
Date: 07-07-2021
Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
DOI: 10.1038/S41594-023-01021-8
Abstract: The genomic binding sites of the transcription factor (TF) and tumor suppressor p53 are unusually erse with regard to their chromatin features, including histone modifications, raising the possibility that the local chromatin environment can contextualize p53 regulation. Here, we show that epigenetic characteristics of closed chromatin, such as DNA methylation, do not influence the binding of p53 across the genome. Instead, the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated histone 3 lysine 4 (H3K4), thereby preferentially localizing to those p53 sites that reside in closed chromatin, whereas it is deterred from accessible chromatin by H3K4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to affect gene expression as a function of the local chromatin state. These findings link H3K4 methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors that locally modulate TF function.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-06-2020
Abstract: Cell identity is defined by gene expression patterns that are established through the binding of specific transcription factors. However, nucleosomal units limit access of transcription factors to specific DNA motifs within the mammalian genome. To study how transcription factors bind such chromatinized, nucleosome-embedded motifs, Michael et al. focused on the pluripotency factors OCT4 and SOX2. They systematically quantified the relative affinities of these factors at different motif positions throughout the nucleosome, enabling structure determination of OCT4-SOX2–bound nucleosomes by cryo–electron microscopy. OCT4 and SOX2 bound cooperatively to strengthen DNA-binding affinity and resulted in DNA distortions that destabilized the nucleosome. This analysis reveals position-dependent binding modes that were validated in vivo, providing insights on how transcription factors read out chromatinized motifs. Science , this issue p. 1460
Publisher: Public Library of Science (PLoS)
Date: 12-2015
Publisher: Wiley
Date: 26-06-2012
Publisher: eLife Sciences Publications, Ltd
Date: 13-07-2016
DOI: 10.7554/ELIFE.15082
Abstract: We previously identified Wiz in a mouse screen for epigenetic modifiers. Due to its known association with G9a/GLP, Wiz is generally considered a transcriptional repressor. Here, we provide evidence that it may also function as a transcriptional activator. Wiz levels are high in the brain, but its function and direct targets are unknown. ChIP-seq was performed in adult cerebellum and Wiz peaks were found at promoters and transcription factor CTCF binding sites. RNA-seq in Wiz mutant mice identified genes differentially regulated in adult cerebellum and embryonic brain. In embryonic brain most decreased in expression and included clustered protocadherin genes. These also decreased in adult cerebellum and showed strong Wiz ChIP-seq enrichment. Because a precise pattern of protocadherin gene expression is required for neuronal development, behavioural tests were carried out on mutant mice, revealing an anxiety-like phenotype. This is the first evidence of a role for Wiz in neural function.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2016
DOI: 10.1038/SREP25004
Abstract: The number of reports of paternal epigenetic influences on the phenotype of offspring in rodents is increasing but the molecular events involved remain unclear. Here, we show that haploinsufficiency for the histone 3 lysine 9 methyltransferase Setdb1 in the sire can influence the coat colour phenotype of wild type offspring. This effect occurs when the allele that directly drives coat colour is inherited from the dam, inferring that the effect involves an “ in trans ” step. The implication of this finding is that epigenetic state of the sperm can alter the expression of genes inherited on the maternally derived chromosomes. Whole genome bisulphite sequencing revealed that Setdb1 mutant mice show DNA hypomethylation at specific classes of transposable elements in the sperm. Our results identify Setdb1 as a paternal effect gene in the mouse and suggest that epigenetic inheritance may be more likely in in iduals with altered levels of epigenetic modifiers.
Publisher: Springer Science and Business Media LLC
Date: 2013
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.BBR.2018.06.019
Abstract: Autism spectrum disorder (ASD) is a heterogeneous and highly heritable condition with multiple aetiologies. Although the biological mechanisms underlying ASD are not fully understood, evidence suggests that dysregulation of serotonergic systems play an important role in ASD psychopathology. Preclinical models using mice with altered serotonergic neurotransmission may provide insight into the role of serotonin in behaviours relevant to clinical features of ASD. For ex le, BALB/c mice carry a loss-of-function single nucleotide polymorphism (SNP C1473 G) in tryptophan hydroxylase 2 (Tph2), which encodes the brain-specific isoform of the rate-limiting enzyme for serotonin synthesis, and these mice frequently have been used to model symptoms of ASD. In this study, juvenile male BALB/c (G/G loss-of-function variant) and C57BL/6 J (C/C wild type variant) mice, were exposed to the three-chamber sociability test, and one week later to the elevated plus-maze (EPM). Tryptophan hydroxylase 2 (TPH2) activity was measured following injection of the aromatic amino acid decarboxylase (AADC)-inhibitor, NSD-1015, and subsequent HPLC detection of 5-hydroxytryptophan (5-HTP) within subregions of the dorsal raphe nucleus (DR) and median raphe nucleus (MnR). The BALB/c mice showed reduced social behaviour and increased anxious behaviour, as well as decreased 5-HTP accumulation in the rostral and mid-rostrocaudal DR. In the full cohort of mice, TPH2 activity in the mid-rostrocaudal DR was correlated with anxious behaviour in the EPM, however these correlations were not statistically significant within each strain, suggesting that TPH2 activity was not directly associated with either anxiety or sociability. Further research is therefore required to more fully understand how serotonergic systems are involved in mouse behaviours that resemble some of the clinical features of ASD.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Publisher: Elsevier BV
Date: 11-2018
Location: Switzerland
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