ORCID Profile
0000-0001-5192-3727
Current Organisations
Leibniz-Zentrum für Agrarlandschaftsforschung
,
Altos Labs
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Publisher: Springer Science and Business Media LLC
Date: 19-04-2016
Publisher: Public Library of Science (PLoS)
Date: 25-02-2014
Publisher: Research Square Platform LLC
Date: 28-12-2020
DOI: 10.21203/RS.3.RS-120562/V1
Abstract: Cellular senescence is a fate-determined state, accompanied by reorganization of heterochromatin. While lineage-appropriate genes can be temporarily repressed through facultative heterochromatin, stable silencing of lineage-inappropriate genes often involves the constitutive heterochromatic mark, histone H3K9me3. The fate of these heterochromatic genes during the chromatin reorganization accompanying senescence is unclear. Here we show a small number of lineage-inappropriate genes are derepressed in senescent cells from H3K9me3 regions that gain open chromatin marks. DNA FISH experiments reveal that these gene loci, which are tightly condensed at the nuclear periphery in proliferative cells, are physically decompacted during senescence. Among these gene loci, NLRP3 is predominantly expressed in immune cells, such as macrophages, where it resides within an open topologically associated domain (TAD). In contrast, NLRP3 is derepressed in senescent fibroblasts, potentially due to the local disruption of the H3K9me3-rich TAD that contains it. The role of NLRP3 has been implicated in the lification of inflammatory cytokine signalling in senescence and aging, underscoring the functional relevance of gene induction from ‘permissive’ H3K9me3 regions in senescent cells.
Publisher: Elsevier BV
Date: 02-2022
Publisher: Springer Science and Business Media LLC
Date: 09-05-2018
DOI: 10.1038/S41467-018-04283-9
Abstract: Senescent cells interact with the surrounding microenvironment achieving erse functional outcomes. We have recently identified that NOTCH1 can drive ‘lateral induction’ of a unique senescence phenotype in adjacent cells by specifically upregulating the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. NOTCH signalling suppresses SAHF and increased chromatin accessibility in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, drive similar chromatin architectural changes in adjacent cells through cell–cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in multiple human cancers. Thus, HMGA1 is involved not only in SAHFs but also in RIS-driven chromatin accessibility. In conclusion, this study identifies that the JAG1–NOTCH–HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2201
DOI: 10.1038/S41467-019-13753-7
Abstract: The architectural protein CTCF is a mediator of chromatin conformation, but how CTCF binding to DNA is orchestrated to maintain long-range gene expression is poorly understood. Here we perform RNAi knockdown to reduce CTCF levels and reveal a shared subset of CTCF-bound sites are robustly resistant to protein depletion. The ‘persistent’ CTCF sites are enriched at domain boundaries and chromatin loops constitutive to all cell types. CRISPR-Cas9 deletion of 2 persistent CTCF sites at the boundary between a long-range epigenetically active (LREA) and silenced (LRES) region, within the Kallikrein ( KLK ) locus, results in concordant activation of all 8 KLK genes within the LRES region. CTCF genome-wide depletion results in alteration in Topologically Associating Domain (TAD) structure, including the merging of TADs, whereas TAD boundaries are not altered where persistent sites are maintained. We propose that the subset of essential CTCF sites are involved in cell-type constitutive, higher order chromatin architecture.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2018
Publisher: Springer Science and Business Media LLC
Date: 27-11-2020
DOI: 10.1038/S41467-020-19878-4
Abstract: Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in human diploid fibroblasts is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks often at the 3′ end of a subset of active genes. RAS-induced de novo cohesin peaks are transcription-dependent and enriched for senescence-associated genes, exemplified by IL1B , where de novo cohesin binding is involved in new loop formation. Similar IL1B induction with de novo cohesin appearance and new loop formation are observed in terminally differentiated macrophages, but not TNFα-treated cells. These results suggest that RAS-induced senescence represents a cell fate determination-like process characterised by a unique gene expression profile and 3D genome folding signature, mediated in part through cohesin redistribution on chromatin.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2221
Publisher: Elsevier
Date: 2017
Publisher: Cold Spring Harbor Laboratory
Date: 06-11-2019
DOI: 10.1101/832873
Abstract: Bivalent chromatin marks developmental promoters in pluripotent cells, yet their targeting and precise impact on lineage commitment remains unclear. We uncover Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) as epigenetic priming factors, establishing chromatin bivalency. Single-cell transcriptomics and differentiation assays reveal Dppa2/4 double knockout embryonic stem cells fail to exit pluripotency and differentiate efficiently. Dppa2/4 associate with COMPASS and Polycomb complexes and are required to recruit and maintain their binding at a subset of developmentally important bivalent promoters which are characterised by low expression and poised RNA polymerase. Consequently, upon Dppa2/4 knockout, these dependent promoters gain DNA methylation and are unable to be activated upon differentiation. Our findings uncover a novel targeting principle for bivalency to developmental promoters, poising them for future lineage specific activation.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2020
Publisher: Elsevier BV
Date: 05-2016
Publisher: Elsevier BV
Date: 2020
Publisher: Frontiers Media SA
Date: 23-05-2016
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NG.3662
Abstract: G-quadruplex (G4) structural motifs have been linked to transcription, replication and genome instability and are implicated in cancer and other diseases. However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context. Herein we address this through the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5' UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number lifications, such as MYC. Strikingly, de novo and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor-induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.
Publisher: Cold Spring Harbor Laboratory
Date: 30-10-2019
DOI: 10.1101/823831
Abstract: Senescence is a phenotypic state of stable proliferative arrest, typically occurring in lineage-committed cells and triggered by various stimuli. It is generally accompanied by activation of a secretory program (senescence-associated secretory phenotype, SASP), which modulates both local (tissue microenvironment) and systemic (ageing) homeostasis 1,2 . Enhancer-promoter interactions play a key role in gene regulation 3–5 , facilitated by chromatin loops, mostly formed via CCCTC binding factor (CTCF) and cohesin tethering 6–8 . The three-dimensional chromatin structure of senescent cells has been characterised 9–11 mostly in terms of macro-domain structures, but its relevance in gene expression remains elusive. Here, we use Hi-C and capture Hi-C 12,13 to show that oncogenic HRAS-induced senescence (RIS) in human diploid fibroblasts (HDFs) is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks at the 3’ end of a subset of active genes, reminiscent of the transcription-driven ‘cohesin islands’ recently discovered in mouse embryonic fibroblasts deficient in both CTCF and the cohesin release factor Wings apart-like (Wapl) 14 . RIS de novo cohesin peaks are also transcription-dependent and enriched for SASP genes, as exemplified by IL1B , where de novo cohesin binding is involved in new loop formation. Cytokine induction is associated with similar cohesin islands appearance and enhancer-promoter rewiring during the terminal differentiation of monocytes to macrophages 15 , but not upon acute TNFα treatment of HDFs 16 . These results suggest that RIS represents a fate-determined process in which gene expression is regulated beyond the cell type specific 3D chromatin framework, in part through cohesin redistribution.
Publisher: Cold Spring Harbor Laboratory
Date: 02-11-2017
DOI: 10.1101/212829
Abstract: Senescent cells interact with the surrounding microenvironment achieving erse functional outcomes. In addition to autocrine and paracrine signalling mediated by factors of the senescence-associated secretory phenotype, we have recently identified that NOTCH1 can drive ‘lateral induction’ of a unique form of senescence in adjacent cells through specific induction of the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure both autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells in culture exhibit a massive increase in nucleosome-free regions (NRFs). NOTCH signalling suppresses both SAHF and NFR formation in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, also drive similar chromatin architectural changes in adjacent cells through cell-cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in a range of human cancers. Thus, HMGA1 is involved not only in SAHFs, but also RIS-specific NFR formation. In conclusion, this study identifies that the JAG1-NOTCH-HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.
Publisher: EMBO
Date: 28-12-2020
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Aled Parry.