MacroH2A in Stem Cells: A Story Beyond Gene Repression

Creppe, Catherine; Posavec, Melanija; Douet, Julien; Buschbeck, Marcus

doi:10.2217/epi.12.8

Cited by 37 publications

(35 citation statements)

References 53 publications

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“…While the genomic distribution of macroH2A correlates with suppression of transcriptional activity (Changolkar and Pehrson, 2006;Changolkar et al, 2010;Gamble et al, 2010), it is in some cases required for signal-induced gene activation (discussed in Creppe et al, 2012b). The repressive function of macroH2A proteins has been primarily associated with cancer.…”

Section: Introductionmentioning

confidence: 99%

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

Douet

Corujo

Malinverni

et al. 2017

Journal of Cell Science

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Genetic loss-of-function studies on development, cancer and somatic cell reprogramming have suggested that the group of macroH2A histone variants might function through stabilizing the differentiated state by a yet unknown mechanism. Here, we present results demonstrating that macroH2A variants have a major function in maintaining nuclear organization and heterochromatin architecture. Specifically, we find that a substantial amount of macroH2A is associated with heterochromatic repeat sequences. We further identify macroH2A on sites of interstitial heterochromatin decorated by histone H3 trimethylated on K9 (H3K9me3). Loss of macroH2A leads to major defects in nuclear organization, including reduced nuclear circularity, disruption of nucleoli and a global loss of dense heterochromatin. Domains formed by DNA repeat sequences are disorganized, expanded and fragmented, and mildly re-expressed when depleted of macroH2A. At the molecular level, we find that macroH2A is required for the interaction of repeat sequences with the nucleostructural protein lamin B1. Taken together, our results argue that a major function of macroH2A histone variants is to link nucleosome composition to higher-order chromatin architecture.

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Section: Introductionmentioning

confidence: 99%

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

Douet

Corujo

Malinverni

et al. 2017

Journal of Cell Science

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“…MacroH2A1 plays important roles in either positively or negatively regulating transcription by recruiting transcriptional coregulators such as PARP-1, PELP1, CBP and HDAC1 (Chakravarthy et al, 2005; Chen et al, 2014; Gamble et al, 2010; Hussey et al, 2014). MacroH2A1 functions in a variety of physiological and pathological processes including senescence, tumor suppression, inhibiting proliferation and inhibiting stem cell reprogramming (Cantariño et al, 2013; Creppe et al, 2012; Gamble and Kraus, 2010; Kreiling et al, 2011; Novikov et al, 2011; Sporn et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype

et al. 2015

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SUMMARY Oncogene-induced senescence (OIS) is a tumor suppressive mechanism typified by stable proliferative arrest, a persistent DNA damage response and the senescence-associated secretory phenotype (SASP), which helps to maintain the senescent state and triggers bystander senescence in a paracrine fashion. Here we demonstrate that the tumor suppressive histone variant macroH2A1 is a critical component of the positive feedback loop that maintains SASP gene expression and triggers the induction of paracrine senescence. MacroH2A1 undergoes dramatic genome-wide relocalization during OIS, including its removal from SASP gene chromatin. The removal of macroH2A1 from SASP genes results from a negative feedback loop activated by SASP-mediated endoplasmic reticulum stress. Endoplasmic reticulum stress leads to increased reactive oxygen species and persistent DNA damage response including activation of ATM, which mediates removal macroH2A1 from SASP genes. Together, our findings indicate that macroH2A1 is a critical control point for the regulation of SASP gene expression during senescence.

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“…10,11 Based on these observations, it was initially suggested that the major function of macroH2A was that of transcriptional repression. However, evidence has accumulated ever since indicating that macroH2A is associated to the active state of a subset of genes, 10,12,13 suggesting that it might play a general structural role that, if perturbed, could affect transcription.…”

Section: Introductionmentioning

confidence: 99%

The characterization of macroH2A beyond vertebrates supports an ancestral origin and conserved role for histone variants in chromatin

et al. 2016

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Histone variants play a critical role in chromatin structure and epigenetic regulation. These "deviant" proteins have been historically considered as the evolutionary descendants of ancestral canonical histones, helping specialize the nucleosome structure during eukaryotic evolution. Such view is now challenged by 2 major observations: first, canonical histones present extremely unique features not shared with any other genes; second, histone variants are widespread across many eukaryotic groups. The present work further supports the ancestral nature of histone variants by providing the first in vivo characterization of a functional macroH2A histone (a variant long defined as a specific refinement of vertebrate chromatin) in a non-vertebrate organism (the mussel Mytilus) revealing its recruitment into heterochromatic fractions of actively proliferating tissues. Combined with in silico analyses of genomic data, these results provide evidence for the widespread presence of macroH2A in metazoan animals, as well as in the holozoan Capsaspora, supporting an evolutionary origin for this histone variant lineage before the radiation of Filozoans (including Filasterea, Choanoflagellata and Metazoa). Overall, the results presented in this work help configure a new evolutionary scenario in which histone variants, rather than modern "deviants" of canonical histones, would constitute ancient components of eukaryotic chromatin.

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MacroH2A in Stem Cells: A Story Beyond Gene Repression

Cited by 37 publications

References 53 publications

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype

The characterization of macroH2A beyond vertebrates supports an ancestral origin and conserved role for histone variants in chromatin

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