The mouse HP1 proteins are essential for preventing liver tumorigenesis

Saksouk, Nehmé; Hajdari, Shefqet; Pratlong, Marine; Barrachina, Célia; Graber, Céline; Zavoriti, Aliki; Sarrazin, Amélie; Pirot, Nelly; Noël, Jean-Yohan; Khellaf, Lakhdar; Fabbrizio, Eric; Julien, Éric; Cammas, Florence

doi:10.1101/441279

Cited by 4 publications

(6 citation statements)

References 67 publications

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“…A prediction of this simple model is that the chromatin fibers connecting the periphery to the internal domains are "spring-loaded" and deletion of HP1 proteins, which removes one of the forces driving aggregation, would lead to movement of the internal domains towards the periphery as the fibres relax. This is, in fact, what is observed in HP1α/β/γ null BMEL cells ( Figure 3D in 175 ). HP1α/β/γ null BMEL nuclei also show a reduction in H3K9me3, albeit many nuclei still possess dense constitutively heterochromatic domains -mostly located at the periphery -indicating that other interactions, in addition to the HP1-H3K9me3 interaction, are involved in macro-phase separation of constitutive heterochromatin.…”

Section: Hp1-mediated Bridging Of H3k9me2/3 Nucleosome Fibres and Comsupporting

confidence: 81%

“…To test the role of HP1 proteins in compartmentalisation it would necessary to delete all three HP1 proteins in mammalian cells. HP1α/β/γ null ES die around a week after deletion of the genes (unpublished result), but conditional deletion of all three HP1 isotypes has been achieved in bi-potential mouse embryonic liver (BMEL) cells (175). BMEL cells represent a system to test the role of heterochromatin-like domains/complexes on compartmentalization seen in Hi-C maps (is there (partial) collapse of B-type compartments in HP1α/β/γ null BMEL cells?)…”

Section: Hp1-mediated Bridging Of H3k9me2/3 Nucleosome Fibres and Commentioning

confidence: 99%

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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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Section: Hp1-mediated Bridging Of H3k9me2/3 Nucleosome Fibres and Comsupporting

confidence: 81%

Section: Hp1-mediated Bridging Of H3k9me2/3 Nucleosome Fibres and Commentioning

confidence: 99%

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

Singh

Newman²

2019

Preprint

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“…This is, in fact, what is observed in HP1α/β/γ null BMEL cells ( fig. 3D in [223]). HP1α/β/γ null BMEL nuclei also show a reduction in H3K9me3, albeit many nuclei still possess dense constitutively heterochromatic domains, indicating that other interactions, in addition to the HP1-H3K9me3 interaction, are involved in macrophase separation of constitutive heterochromatin.…”

Section: Discussionmentioning

confidence: 98%

“…HP1α/β/γ null ES die around a week after deletion of the genes (J. Sharif, A.G. Newman, P.B. Singh 2019, unpublished result), but conditional deletion of all three HP1 isotypes has been achieved in bi-potential mouse embryonic liver (BMEL) cells [223]. BMEL cells represent a system to test the role of heterochromatin-like domains/complexes on compartmentalization seen in Hi-C maps (is there (partial) collapse of B-type compartments in HP1α/β/ γ null BMEL cells?)…”

Section: Discussionmentioning

confidence: 99%

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

Singh

Newman

2020

R. Soc. open sci.

View full text Add to dashboard Cite

The relationship between compartmentalization 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 discovery of position-effect variegation in 1930 went on to show that heterochromatin is a cytologically visible state of heritable (epigenetic) gene repression. Current insights into compartmentalization 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 compartmentalization seen in Hi-C maps is owing 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 (0.1–5 Mb) heterochromatin -like domains and smaller (less than 100 kb) complexes. The well-documented ability of HP1 proteins to function as bridges between H3K9me2/3-marked nucleosomes contributes to polymer–polymer phase separation 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 subcompartment that emerges from contacts between large KRAB-ZNF heterochromatin -like domains. Further, mutational analyses have revealed a finer, innate, compartmentalization in Hi-C experiments that probably 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 evolutionarily conserved paradigm—could drive and generate the fundamental compartmentalization 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 alterations occurring upon loss of PA28γ neither impact cell viability nor induce a strong phenotype, as observed upon HP1β depletion in MEF cells (Bosch-Presegue et al, 2017) or in HP1-triple knockout in hepatocytes (Saksouk et al, 2020). However, our data reveal a change in cell cycle progression with a decrease in S-phase duration, suggesting that the accessibility and/or the progression of the replication machinery could be facilitated by the decompaction of the most condensed chromatin domains.…”

Section: Discussionmentioning

confidence: 99%

The 20S proteasome activator PA28γ controls the compaction of chromatin

Fesquet

Llères

Grimaud

et al. 2019

Preprint

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The nuclear PA28γ is known to activate the 20S proteasome, but its precise cellular functions remains unclear. Here, we identify PA28γ as a key factor that structures heterochromatin. We find that in human cells, a fraction of PA28γ-20S proteasome complexes localizes within HP1-linked heterochromatin foci. Our biochemical studies show that PA28γ interacts with HP1 proteins, particularly HP1β, which recruits the PA28γ-20S proteasome complexes to heterochromatin. Loss of PA28γ does not modify the localization of HP1β, its mobility within nuclear foci, or the level of H3K9 tri-methylation, but reduces H4K20 mono-and trimethylation, modifications involved in heterochromatin establishment. Concordantly, using a quantitative FRET-based microscopy assay to monitor nanometer-scale proximity between nucleosomes in living cells, we find that PA28γ regulates nucleosome proximity within heterochromatin, and thereby controls its compaction. This function of PA28γ is independent of the 20S proteasome. Importantly, HP1β on its own is unable to drive heterochromatin compaction without PA28γ. Combined, our data reveal an unexpected chromatin structural role of PA28γ, and provide new insights into the mechanism that controls HP1β-mediated heterochromatin compaction.

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The mouse HP1 proteins are essential for preventing liver tumorigenesis

Abstract: 20Chromatin organization is essential for appropriate interpretation of the genetic information. 21Here, we demonstrated that the chromatin associated proteins HP1 are dispensable for cell 22 multiple chromatin-associated events. 33

Cited by 4 publications

References 67 publications

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

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

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

The 20S proteasome activator PA28γ controls the compaction of chromatin

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