Chromatin domains rich in inheritance

Reinberg, Danny; Vales, L D

doi:10.1126/science.aat7871

Cited by 139 publications

(152 citation statements)

References 14 publications

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“…Perhaps this might seem contradictory to the prevailing notion of the histone mark as a repressor. However, the delayed change of the histone modification after transcriptional change is consistent with previous reports showing the same relationship upon global induction of cellular stimuli (Hosogane et al, 2013;Kashyap et al, 2011), and with the mechanistic property of the repressive state as an epigenetic memory (Reinberg and Vales, 2018). Also accumulative evidence has shown that PRC2 has almost no effect on gene expression in a certain context (Riising et al, 2014).…”

Section: The H3k27me3 Mark Reflects the Gene Expressionsupporting

confidence: 90%

Controlling gene activation by enhancers through a drug-inducible topological insulator

Tsujimura

Takase

Yoshikawa

et al. 2019

Preprint

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AbstractWhile regulation of gene-enhancer interaction is better understood, its application remains limited. Here, we reconstituted arrays of CTCF binding sites and devised a synthetic topological insulator with tetO for chromatin-engineering (STITCH). By coupling STITCH with tetR linked to the KRAB domain to induce heterochromatin and disable the insulation, we developed a drug-inducible system to control gene activation by enhancers. We applied this to dissect MYC regulation in human pluripotent stem cells. Insertion of STITCH between MYC and the enhancer down-regulated MYC and affected its target transcriptome. Progressive mutagenesis of STITCH led to preferential escalation of the gene-enhancer interaction, corroborating the strong insulation ability of STITCH. The STITCH insertion altered epigenetic states around MYC. Time-course analysis by drug induction uncovered deposition and removal of H3K27me3 repressive marks follows and reflects, but does not precede and determine, the expression change. Thus the tool provided important insights in gene regulation, demonstrating its potency.

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Section: The H3k27me3 Mark Reflects the Gene Expressionsupporting

confidence: 90%

Controlling gene activation by enhancers through a drug-inducible topological insulator

Tsujimura

Takase

Yoshikawa

et al. 2019

Preprint

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“…Genome function and cellular identity are maintained through the structural organization of chromatin domains that either facilitate or impede transcription. The presence of specific histone post-translational modifications (PTMs) within these chromatin domains not only correlate with a given transcription status, but also facilitate the formation of repressive chromatin structures that impact gene expression (Reinberg and Vales, 2018). In order to maintain the integrity of these gene expression programs through cell division, the molecular features defining these chromatin structures must be transmitted, rather than established anew.…”

Section: Introductionmentioning

confidence: 99%

Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication

Escobar

Oksuz

Descostes

et al. 2018

Preprint

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Chromatin domains and their associated structures must be faithfully inherited through cellular division to maintain cellular identity. Yet, accessing the localized strategies preserving chromatin domain inheritance, specifically the transfer of parental, preexisting nucleosomes with their associated post-translational modifications (PTMs) during DNA replication is challenging in living cells. We devised an inducible, proximity-dependent labeling system to irreversibly mark replication-dependent H3.1 and H3.2 histone-containing nucleosomes at single desired loci in mouse embryonic stem cells such that their fate after DNA replication could be followed. Strikingly, repressed chromatin domains are preserved through the local re-deposition of parental nucleosomes. In contrast, nucleosomes decorating active chromatin domains do not exhibit such preservation. Notably, altering cell fate leads to an adjustment in the positional inheritance of parental nucleosomes that reflects the corresponding changes in chromatin structure. These findings point to important mechanisms that contribute to parental nucleosome segregation to preserve cellular identity.

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“…For one, the mammalian Pc homologue CBX2, like HP1 proteins, can promote phase separation that is dependent upon amino-acids in CBX2 necessary for nucleosome fibre compaction (197,198). Second, the histone modifications H3K9me2/3 and H3K27me3 are diagnostic for HP1-and Pc-dependent domains/complexes respectively (Table 1) (199) and are used, inter alia, to define B-type compartmental domains (170). Given that H3K9me2/3 and H3K27me3 are the only histone modifications that are truly epigenetic (199) we suggest that the B-type compartmental domains generated by HP1-and Pc-dependent domains/complexes are epigenetic compartmental domains (ECDs) that drive the compartmentalisation seen in Hi-C maps in the same way that cytologically-visible compartmental segregation is driven solely by heterochromatin (178).…”

Section: "Epigenetic Compartmental Domains" (Ecds) and The Regulationmentioning

confidence: 99%

“…Pc-dependent domains/complexes respectively (Table 1) 199 and are used, inter alia, to define B-type compartmental domains 170 . Given that H3K9me2/3 and H3K27me3 are the only histone modifications that are truly epigenetic 199 we suggest that the B-type compartmental domains generated by HP1-and Pc-dependent domains/complexes are epigenetic compartmental domains (ECDs) that drive the compartmentalisation seen in Hi-C maps in the same way that cytologically-visible compartmental segregation is driven solely by heterochromatin 177 .…”

Section: "Epigenetic Compartmental Domains" (Ecds) and The Regulationmentioning

confidence: 99%

On the relation of phase separation and Hi-C maps to epigenetics

Singh

Newman²

2019

Preprint

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The relationship between compartmentalisation of the genome and epigenetics is long and hoary. In 1928 Heitz defined heterochromatin as the largest differentiated chromatin compartment in eukaryotic nuclei. Müller's (1930) discovery of position-effect variegation (PEV) went on to show that heterochromatin is a cytologically-visible state of heritable (epigenetic) gene repression. Current insights into compartmentalisation have come from a high-throughput top-down approach where contact frequency (Hi-C) maps revealed the presence of compartmental domains that segregate the genome into heterochromatin and euchromatin. It has been argued that the compartmentalisation seen in Hi-C maps is due to the physiochemical process of phase separation. Oddly, the insights provided by these experimental and conceptual advances have remained largely silent on how Hi-C maps and phase separation relate to epigenetics. Addressing this issue directly in mammals we have made use of a bottom-up approach starting with the hallmarks of constitutive heterochromatin, heterochromatin protein 1 (HP1) and its binding partner the H3K9me2/3 determinant of the histone code. They are key epigenetic regulators in eukaryotes. Both hallmarks are also found outside mammalian constitutive heterochromatin as constituents of larger (0.1-5Mb) heterochromatin-like domains and smaller (less than 100Kb) complexes. The well-documented ability of HP1 proteins to function as bridges between H3K9me2/3-marked nucleosomes enables cross-linking within and between chromatin fibres that contributes to polymer-polymer phase separation (PPPS) that packages epigenetically-heritable chromatin states during interphase. Contacts mediated by HP1 "bridging" are likely to have been detected in Hi-C maps, as evidenced by the B4 heterochromatic sub-compartment that emerges from contacts between large KRAB-ZNF heterochromatin-like domains. Further, mutational analyses have revealed a finer, innate, compartmentalisation in Hi-C experiments that likely reflect contacts involving smaller domains/complexes. Proteins that bridge (modified) DNA and histones in nucleosomal fibres -where the HP1-H3K9me2/3 interaction represents the most evolutionarilyconserved paradigm -could drive and generate the fundamental compartmentalisation of the interphase nucleus.This has implications for the mechanism(s) that maintains cellular identity, be it a terminally-differentiated fibroblast or a pluripotent embryonic stem cell.

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Chromatin domains rich in inheritance

Abstract: Only certain histone posttranslational modifications qualify as being epigenetic

Cited by 139 publications

References 14 publications

Controlling gene activation by enhancers through a drug-inducible topological insulator

Controlling gene activation by enhancers through a drug-inducible topological insulator

Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication

On the relation of phase separation and Hi-C maps to epigenetics

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