The histone variant macroH2A is an epigenetic regulator of key developmental genes

Buschbeck, Marcus; Uribesalgo, Iris; Wibowo, Indra; Rué, Pau; Martin, David L.; Gutiérrez, Arantxa; Morey, Lluís; Guigó, Roderic; López‐Schier, Hernán; Croce, Luciano Di

doi:10.1038/nsmb.1665

Cited by 167 publications

(182 citation statements)

References 38 publications

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“…While macroH2A is highly enriched on the inactive X chromosome, 57 H2A-Bbd is depleted from this chromosome. In addition, macroH2A associates with several inactive promoters, 58,59 whether H2A-Bbd is expected to be found on active genes. 60 Because H2A.Z is found on active promoters, it will be very interesting to characterize the dynamics and interrelations between these three H2A variants.…”

Section: What Recruits and Removes The Randomly-incorporatedmentioning

confidence: 99%

Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

Hardy

Robert²

2010

Epigenetics

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Despite the fact that it has been intensively studied during the last decade, the function of the histone variant H2A.Z remains enigmatic. In the last few years, we and others have determined the localization of H2A.Z in various organisms. These studies have revealed that H2A.Z occupies different well defined regions in the genome. Interestingly, H2A.Z occupies the promoters and regulatory regions of active genes, as well as constitutive and facultative heterochromatin. The localization of H2A.Z on genomic regions with so diverse functions suggests that the roles of H2A.Z are multiple, only increasing the mystery around this molecule. The way H2A.Z finds its way into these regions is not fully understood but mechanisms that direct the specific incorporation of H2A.Z in promoters and enhancers have been well described. In this Point of View, we review our recent work suggesting that non-targeted incorporation, coupled to targeted depletion of H2A.Z, is a novel mechanism for localizing H2A.Z to some regions. We propose that the various functions of H2A.Z may be a consequence of the mechanism used for its incorporation, as well as its interactions with other histone variants.

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Section: What Recruits and Removes The Randomly-incorporatedmentioning

confidence: 99%

Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

Hardy

Robert²

2010

Epigenetics

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“…In the maternal pronucleus, the unique histones H1foo and macroH2A are down-regulated only after the first mitotic division (Chang et al, 2005). MacroH2A remains repressed until the morula stage and associates with the PRC2 complex (Buschbeck et al, 2009), indicating that its expression may be associated with gene silencing (Chang et al, 2005).…”

Section: Reprogramming and Preimplantation Development (Pid)mentioning

confidence: 99%

Natural and artificial routes to pluripotency

Krueger¹,

Swanson²,

Tanasijevic³

et al. 2010

Int. J. Dev. Biol.

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Pluripotent cells of the blastocyst inner cell mass (ICM) and their in vitro derivatives, embryonic stem (ES) cells, contain genomes in an epigenetic state that are poised for subsequent differentiation. Their chromatin is hyperdynamic in nature and relatively uncondensed. In addition, a large number of genes are expressed at low levels in both ICM and ES cells. Also, the chromatin of naturally pluripotent cells contains specialized histone modification patterns such as bivalent domains, which mark genes destined for later developmentally-regulated expression states. Female pluripotent cells contain X chromosomes that have yet to undergo the process of X chromosome inactivation. Collectively, these features of very early embyronic chromatin are required for the successful specification and production of differentiated cell lineages. Artificial reprogramming methods such as somatic nuclear transfer (SCNT), ES cell fusion-mediated reprogramming (FMR), and induced pluripotency (iPS) yield pluripotent cells that recapitulate many features of naturally pluripotent cells, including many of their epigenetic features. However, the route to pluripotent epigenomic states in artificial pluripotent cells differs drastically from that of their natural counterparts. Here, we compare and contrast the differing routes to pluripotency under natural and artificial conditions. In addition, we discuss the intrinsically metastable nature of the pluripotent epigenome and consider epigenetic aspects of reprogramming that may lead to incomplete or inaccurate reprogrammed states. Artificial methods of reprogramming hold immense promise for the development of autologous cell graft sources and for the development of cell culture models for human genetic disorders. However, the utility of artificially reprogrammed cells is highly dependent on the fidelity of the reprogramming process and it is therefore critically important to assess the epigenetic similarities between embryonic and induced pluripotent stem cells.

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“…[33][34][35] Thus, we decided to investigate whether mH2A2 has a functional role in erythroid differentiation. Therefore, we infected the pro-erythroblast cell line I/11 with control shRNA or one of two different mH2A2 shRNAs ( Figure 6a) and then analyzed for differentiation by flow cytometry.…”

Section: Em (E) Quantitative Analysis (Paired T-test Two-tailed) Omentioning

confidence: 99%

Epo-induced erythroid maturation is dependent on Plcγ1 signaling

et al. 2014

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Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells (HSCs) into more committed progenitors and finally into erythrocytes. Binding of erythropoietin (Epo) to its receptor (EpoR) is required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Janus kinase 2 (Jak2) tyrosine kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (Plcγ1) is activated downstream of EpoR-Jak2 independently of Stat5. Plcγ1-deficient pro-erythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of Plcγ1 in immunophenotypically defined HSCs (Lin − Sca1 + KIT + CD48 − CD150 + ) severely reduced erythroid development. To identify Plcγ1 effector molecules involved in regulation of erythroid differentiation, we assessed changes occurring at the global transcriptional and DNA methylation level after inactivation of Plcγ1. The top common downstream effector was H2afy2, which encodes for the histone variant macroH2A2 (mH2A2). Inactivation of mH2A2 expression recapitulated the effects of Plcγ1 depletion on erythroid maturation. Taken together, our findings identify Plcγ1 and its downstream target mH2A2, as a 'non-canonical' Epo signaling pathway essential for erythroid differentiation.

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The histone variant macroH2A is an epigenetic regulator of key developmental genes

Cited by 167 publications

References 38 publications

Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

Natural and artificial routes to pluripotency

Epo-induced erythroid maturation is dependent on Plcγ1 signaling

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