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Chromatin states and genomic organization impact replication timing and local patterns [ATAC-seq]

ABSTRACT: Replication timing (RT) associates with genome architecture, while having a mixed relationship to histone marks. By profiling replication at high-resolution and systematically assessing broad and focused histone marks across cell cycle with and without genetic perturbation, we address the causal relationship between histone marks, their associated states and RT. Our approach identified four chromatin states, including a previously uncharacterized H3K36me2 state, that defined 97% of the mappable genome. RT and local replication patterns (e.g., initiation zones) quantitatively associate with chromatin states, histone mark dynamics, and spatial chromatin structure. Furthermore, overexpression of the histone H3 lysine 9/36 tri-demethylase KDM4A impacts RT genome-wide (11%), which is linked to KDM4A-associated histone marks and clusters of enhancer elements. Lastly, replication within H3K36me2-enriched neighborhoods is sensitive to KDM4A overexpression and is controlled at a megabase-scale. These studies establish a critical role for chromatin regulation in regulating RT and the local RT patterns.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176495 | GEO | 2021/09/27

REPOSITORIES: GEO

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Chromatin states and genomic organization impact local replication features and timing [ChIP-seq]

Project description:Replication timing (RT) control is linked to histone modifications (HMs) and genome architecture. However, HM landscape across cell cycle and its relationship with RT and chromatin modifiers have not been comprehensively assessed. Here we perform detailed replication profiling together with cell cycle profiling of multiple HMs, ATAC-seq, and gene expression. We classify 97% of the genome into four gross chromatin states, including a previously uncharacterized intergenic H3K36me2 state. RT and associated replication features (e.g. initiation zones) quantitatively associate with these chromatin states, HM dynamics, and spatial chromatin structure. Furthermore, overexpression of the histone H3 lysine 9/36 tri-demethylase KDM4A impacts RT across 12% of the genome. RT regulation is strongly linked to KDM4A-associated HMs and enhancer-like elements. Lastly, replication within the intergenic H3K36me2 neighborhoods is sensitive to KDM4A overexpression and is controlled as wide megabase-scale units. In conclusion, these studies establish a critical role for chromatin regulation in directing RT genome-wide.

2021-09-27 | GSE175750 | GEO

Chromatin states and genomic organization impact local replication features and timing [Repli-seq]

2021-09-27 | GSE175751 | GEO

Two distinct modes for propagation of histone PTMs across the cell cycle

Project description:Epigenetic states defined by chromatin can be maintained through mitotic cell division. However, it remains unknown how histone-based information is transmitted. Here we combine nascent chromatin capture (NCC) and triple-SILAC labelling to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di- and tri-methylation marks are diluted two-fold upon DNA replication, as a consequence of new histone deposition. Importantly, within one cell cycle all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9me3 and H3K27me3 are propagated by continuous modification of parental and new histones, because the establishment of these marks extends over several cell generations. Together, our results reveal how histone marks propagate and demonstrate that chromatin states oscillate within the cell cycle.

2015-03-30 | PXD001980 | Pride

ASH1L links histone H3 lysine 36 di-methylation to leukemia

Project description:The histone methyltransferases MLL and ASH1L are trithorax-group proteins that interact genetically through undefined molecular mechanisms to regulate developmental and hematopoietic gene expression. Here we show that the lysine 36-dimethyl mark of histone H3 (H3K36me2) written by ASH1L is preferentially bound in vivo by LEDGF, an MLL-associated protein that co-localizes with MLL, ASH1L and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild type MLL proteins to chromatin at key leukemia target genes, and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely KDM2A, an H3K36me2 demethylase and Polycomb-group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies illuminate the molecular mechanisms underlying epigenetic interactions wherein placement, interpretation and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a target for therapeutic intervention. Investigation of multiple transcription factors and histone modification marks in MV4-11 human leukemia cells.

2016-07-01 | E-GEOD-73528 | biostudies-arrayexpress

Accurate recycling of parental histones reproduces the histone modification landscape during DNA replication II

Project description:Chromatin organisation is disrupted genome wide during DNA replication. On newly synthesized DNA, nucleosomes are assembled from new naïve histones and old modified histones. It remains unknown whether the landscape of histone post-translational modifications (PTMs) is copied during DNA replication or the epigenomeis perturbed. Here we develop Chromatin Occupancy after Replication, ChOR-seq, a technology that combines chromatin immunopreciptation of histone marks and purification of newly replicated DNA by streptavidin pull down followed by next generation sequencing. We use this technology to address propagation of epigenetic states across cell division and reveal that accurate recycling of modified parental histones ensures that positional information of histone marks is faithfully reproduced on daughter strands and inherited to daughter cells.

2018-08-23 | GSE110353 | GEO

Accurate recycling of parental histones reproduces the histone modification landscape during DNA replication

Project description:Chromatin organisation is disrupted genome wide during DNA replication. On newly synthesized DNA, nucleosomes are assembled from new naïve histones and old modified histones. It remains unknown whether the landscape of histone post-translational modifications (PTMs) is copied during DNA replication or the epigenomeis perturbed. Here we develop Chromatin Occupancy after Replication, ChOR-seq, a technology that combines chromatin immunopreciptation of histone marks and purification of newly replicated DNA by streptavidin pull-down followed by next generation sequencing. We use this technology to address propagation of epigenetic states across cell division and reveal that accurate recycling of modified parental histones ensures that positional information of histone marks is faithfully reproduced on daughter strands and inherited to daughter cells.

2018-08-23 | GSE110352 | GEO

Accurate recycling of parental histones reproduces the histone modification landscape during DNA replication III

Project description:Chromatin organisation is disrupted genome wide during DNA replication. On newly synthesized DNA, nucleosomes are assembled from new naïve histones and old modified histones. It remains unknown whether the landscape of histone post-translational modifications (PTMs) is copied during DNA replication or the epigenomeis perturbed. Here we develop Chromatin Occupancy after Replication, ChOR-seq, a technology that combines chromatin immunopreciptation of histone marks and purification of newly replicated DNA by streptavidin pull-down followed by next generation sequencing. We use this technology to address propagation of epigenetic states across cell division and reveal that accurate recycling of modified parental histones ensures that positional information of histone marks is faithfully reproduced on daughter strands and inherited to daughter cells.

2018-08-23 | GSE116310 | GEO

Epigenetic regulation of gene expression is instructed by promoter sequence and refined by developmental progression [genomic]

Project description:A large body of literature suggests that local features of chromatin are crucial in determining functional properties of underlying DNA. The extent to which DNA sequence plays an active role in the establishment and maintenance of patterns of histone and DNA modification at promoters in cells and tissues in an adult animal remains poorly understood. Likewise, whether passage through development is required for refinement of transcriptional states and chromatin marks characteristic of fully differentiated adult cells remains unclear. Here we undertook analysis of gene expression along with the genomic distribution of DNA methylation and a set of histone marks in primary tissues derived from different primordial germ layers in adult mice. We find that promoter CpG content correlated strongly with specific repressive mechanisms. Likewise, RNA polymerase II occupancy and active histone marks were omnipresent on CpG rich promoters regardless of transcriptional output and of cell type. However, these same chromatin features cleanly demarcate transcriptional activity on promoters with low CpG content. While these observations imply an instructive role for DNA sequence in establishment and maintenance of epigenetic states, experimental evidence presented here also suggests an additional role for development in refining these features at individual promoters. DNA methylation and a set of histone marks (H3K4me3, H3K9me2 and H3K27me3) were examined in B cells and liver using Nimblegen mouse promoter arrays.

2014-08-31 | E-GEOD-41447 | biostudies-arrayexpress

The lysine demethylase KDM4A controls the cell-cycle expression of replicative canonical histone genes

Project description:Chromatin modulation provides a key checkpoint for controlling cell cycle regulated gene networks. The replicative canonical histone genes are one such gene family under tight regulation during cell division. These genes are most highly expressed during S phase when histones are needed to chromatinize the new DNA template. While this fact has been known for a while, limited knowledge exists about the specific chromatin regulators controlling their temporal expression during cell cycle. Since histones and their associated mutations are emerging as major players in diseases such as cancer, identifying the chromatin factors modulating their expression is critical. The histone lysine tri-demethylase KDM4A is regulated over cell cycle and plays a direct role in DNA replication timing, site-specific rereplication, and DNA amplifications during S phase. Here, we establish an unappreciated role for the catalytically active KDM4A in directly regulating canonical replicative histone gene networks during cell cycle. Of interest, we further demonstrate that KDM4A interacts with proteins controlling histone expression and RNA processing. Together, this study provides a new function for KDM4A in modulating canonical histone gene expression.

2021-10-27 | GSE154684 | GEO

Epigenetic regulation of gene expression is instructed by promoter sequence and refined by developmental progression [expression]

Project description:A large body of literature suggests that local features of chromatin are crucial in determining functional properties of underlying DNA. The extent to which DNA sequence plays an active role in the establishment and maintenance of patterns of histone and DNA modification at promoters in cells and tissues in an adult animal remains poorly understood. Likewise, whether passage through development is required for refinement of transcriptional states and chromatin marks characteristic of fully differentiated adult cells remains unclear. Here we undertook analysis of gene expression along with the genomic distribution of DNA methylation and a set of histone marks in primary tissues derived from different primordial germ layers in adult mice. We find that promoter CpG content correlated strongly with specific repressive mechanisms. Likewise, RNA polymerase II occupancy and active histone marks were omnipresent on CpG rich promoters regardless of transcriptional output and of cell type. However, these same chromatin features cleanly demarcate transcriptional activity on promoters with low CpG content. While these observations imply an instructive role for DNA sequence in establishment and maintenance of epigenetic states, experimental evidence presented here also suggests an additional role for development in refining these features at individual promoters. Gene expression in B cells and liver was measured using Agilent Whole Mouse Genome 4x44 multiplex format oligo arrays.

2014-08-31 | E-GEOD-41449 | biostudies-arrayexpress

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