MacroH2A – An epigenetic regulator of cancer

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

“…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). …”

MacroH2A1.1 and PARP-1 cooperate to regulate transcription by promoting CBP-mediated H2B acetylation

“…The three macroH2A isoforms, macroH2A1.1, macroH2A1.2 and macroH2A2, contain an amino-terminal H2A-like region fused to a macrodomain by a flexible linker. Through their ability to regulate transcription, these histone variants have been implicated in a variety of processes including tumor suppression, inhibition of reprograming and differentiation 1-3 .…”

Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet

“…[8][9][10][11][18][19][20][21][22] MacroH2A1 KO mice have been generated by two independent groups and they both reported mild metabolic effects. 20,21 To understand if macroH2A1 could have systemic effects on fat accumulation and obesity, we challenged macroH2A1 KO mice with a HFD.…”

“…20,21 In the second model, KO for macroH2A1 in a mixed background led to a variable hepatic lipid accumulation in 50% of the females. 22 Therefore, despite compelling in vitro evidence that macroH2A1 modulates gene expression programs involved in cell metabolism, proliferation and differentiation, 9,10 its role at the organism level under nutritional stress conditions, especially during obesity, is not understood. In this study, we challenged macroH2A1 KO mice 20,21 with an obesogenic diet for 12 weeks: we found that genetic ablation of this histone increased leanness, glucose tolerance and energy expenditure, protecting the body against high-fat diet (HFD)-induced obesity.…”

“…7 The transcriptional activity of macroH2A1 has come to take a centre stage in the plasticity of stem cell differentiation and in the pathogenesis of many cancer types. [8][9][10][11] MacroH2A1 is composed of a domain displaying 66% homology with histone H2A, and a domain called macro that is conserved in multiple functionally unrelated proteins throughout the animal kingdom and that can bind in vitro with tight affinity ADP-ribose-like metabolites produced by NAD+-dependent histone deacetylase sirtuins or by polyADP-ribose polymerase enzymes. 12,13 This binding represents a direct molecular interaction between intermediate metabolism and the chromatin, whereby a metabolite can impinge on and tweak gene expression in vitro.…”