Macro domains as metabolite sensors on chromatin

Posavec, Melanija; Timinszky, Gyula; Buschbeck, Marcus

doi:10.1007/s00018-013-1294-4

Cited by 43 publications

(39 citation statements)

References 133 publications

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“…The link between nuclear architecture and cell fate Loss-of-function studies in development, cancer and somatic cell reprogramming have allowed the conclusion that macroH2A proteins contribute to maintaining the differentiated state of a cell by a yet unknown mechanism (reviewed in Posavec et al, 2013). Here, we show that macroH2A is required for the establishment and/ or the maintenance of heterochromatin.…”

Section: Macroh2a Is Essential To Maintain Nuclear Integritymentioning

confidence: 76%

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: Macroh2a Is Essential To Maintain Nuclear Integritymentioning

confidence: 76%

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

Douet

Corujo

Malinverni

et al. 2017

Journal of Cell Science

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“…Historically, macroH2A1 has been implicated in X chromosome inactivation and transcriptional repression: this view has recently been challenged by reports that have linked macroH2A proteins to signal-induced gene activation (7–9). macroH2A1 isoforms have taken center stage in the plasticity of stem cell differentiation and in the pathogenesis of many cancers, providing an exciting, yet poorly understood, link to metabolism and nutrients (10, 11). …”

Section: Introductionmentioning

confidence: 99%

DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression

et al. 2016

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Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear.macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression.

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“…The macroH2A1.1 is generally associated with repressed chromatin, such as the inactive X chromosome [185] and could explain the 4:1 male:female gender distortion present in autism. But because it also contains binding sites for cellular metabolites in through the macrodomain, macroH2A1.1 may have a more dynamic role in the modulation of gene expression in response to environmental signals [186]. Although macroH2A1.1 was identified as an autism candidate gene by a GWAS, no association was found [187].…”

Section: ○ Histone Methylationmentioning

confidence: 99%

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Carrascosa-Romero¹,

Cabo²

2017

Autism - Paradigms, Recent Research and Clinical Applications

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The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one-carbon metabolism cycle), histone variants, and ATP-dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets.

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Macro domains as metabolite sensors on chromatin

Cited by 43 publications

References 133 publications

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

MacroH2A histone variants maintain nuclear organization and heterochromatin architecture

DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

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