The histone variant macroH2A1.1 regulates RNA polymerase II-paused genes within defined chromatin interaction landscapes

Recoules, Ludmila; Heurteau, Alexandre; Raynal, Flavien; Karasu, Nezih; Moutahir, Fatima; Bejjani, Fabienne; Jariel-Encontre, Isabelle; Cuvier, Olivier; Sexton, Tom; Lavigne, Anne-Claire; Bystricky, Kerstin

doi:10.1242/jcs.259456

Cited by 13 publications

(4 citation statements)

References 90 publications

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“…While our epigenomic analysis points out the enrichment of both mH2A1 and mH2A2 at mBE, our data suggest a specific role for mH2A2 as a repressor, consistent with its role as a barrier to iPS reprogramming 23 . Other studies have shown mH2A1 isoforms to be implicated in regulation of enhancers but were limited to one cellular model or a particular mH2A isoform, e.g., mH2A1.2 in skeletal muscle C2C12 56 and mH2A1.1 in MDA-MB-231 cells 57 . Even if our focus was on the functional role of mH2A2 at enhancers, the enrichment of both variants is important to define mBEs and the effect we observed from the dKO MaSC suggests that mBEs function as a fine-tuning mechanism rather than indispensable regulators of normal development.…”

Section: Discussionmentioning

confidence: 99%

MacroH2A histone variants modulate enhancer activity to repress oncogenic programs and cellular reprogramming

et al. 2023

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Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined ‘macro-Bound Enhancers’, that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.

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Section: Discussionmentioning

confidence: 99%

MacroH2A histone variants modulate enhancer activity to repress oncogenic programs and cellular reprogramming

et al. 2023

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“…In a limited case series of morbidly obese patients, the expression of macroH2A1.1 was specifically and massively increased in the adipose tissue, correlating with the BMI 27 . The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD + -derived metabolites, which is not present in macroH2A1.2, which is thought to mediate some of its specific cellular functions such as gene expression and modulation of mitochondrial respiration 28 , 29 . We recently generated a mouse model where the histone variant isoform macroH2A1.1, but not macroH2A1.2, was depleted in the whole body 30 .…”

Section: Introductionmentioning

confidence: 99%

Deficiency of histone variant macroH2A1.1 is associated with sexually dimorphic obesity in mice

Chiodi,

Rappa,

Lo Re

et al. 2023

Sci Rep

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Obesity has a major socio-economic health impact. There are profound sex differences in adipose tissue deposition and obesity-related conditions. The underlying mechanisms driving sexual dimorphism in obesity and its associated metabolic disorders remain unclear. Histone variant macroH2A1.1 is a candidate epigenetic mechanism linking environmental and dietary factors to obesity. Here, we used a mouse model genetically depleted of macroH2A1.1 to investigate its potential epigenetic role in sex dimorphic obesity, metabolic disturbances and gut dysbiosis. Whole body macroH2A1 knockout (KO) mice, generated with the Cre/loxP technology, and their control littermates were fed a high fat diet containing 60% of energy derived from fat. The diet was administered for three months starting from 10 to 12 weeks of age. We evaluated the progression in body weight, the food intake, and the tolerance to glucose by means of a glucose tolerance test. Gut microbiota composition, visceral adipose and liver tissue morphology were assessed. In addition, adipogenic gene expression patterns were evaluated in the visceral adipose tissue. Female KO mice for macroH2A1.1 had a more pronounced weight gain induced by high fat diet compared to their littermates, while the increase in body weight in male mice was similar in the two genotypes. Food intake was generally increased upon KO and decreased by high fat diet in both sexes, with the exception of KO females fed a high fat diet that displayed the same food intake of their littermates. In glucose tolerance tests, glucose levels were significantly elevated upon high fat diet in female KO compared to a standard diet, while this effect was absent in male KO. There were no differences in hepatic histology. Upon a high fat diet, in female adipocyte cross-sectional area was larger in KO compared to littermates: activation of proadipogenic genes (ACACB, AGT, ANGPT2, FASN, RETN, SLC2A4) and downregulation of antiadipogenic genes (AXIN1, E2F1, EGR2, JUN, SIRT1, SIRT2, UCP1, CCND1, CDKN1A, CDKN1B, EGR2) was detected. Gut microbiota profiling showed increase in Firmicutes and a decrease in Bacteroidetes in females, but not males, macroH2A1.1 KO mice. MacroH2A1.1 KO mice display sexual dimorphism in high fat diet-induced obesity and in gut dysbiosis, and may represent a useful model to investigate epigenetic and metabolic differences associated to the development of obesity-associated pathological conditions in males and females.

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“…mH2A1 is enriched at heterochromatin domains on the inactive X chromosome (Xi) [7,8] or on autosomes. Concerning the latter, mH2A1 forms large domains at facultative heterochromatin [9][10][11], to a lesser extent, at constitutive heterochromatin marked with the histone mark H3K9me3 [12], and at silent ribosomal DNA segments (rDNA) [13]. Moreover, in senescent cells, this histone variant is incorporated into Senescence-Associated Heterochromatin Foci (SAHFs) [14], which are composed of both heterochromatin types and pericentromeric DNA regions [15,16].…”

Section: Introductionmentioning

confidence: 99%

Recruitment of the Histone Variant MacroH2A1 to the Pericentric Region Occurs upon Chromatin Relaxation and Is Responsible for Major Satellite Transcriptional Regulation

Recoules,

Tanguy Le Gac,

Moutahir

et al. 2023

Cells

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Heterochromatin formation plays a pivotal role in regulating chromatin organization and influences nuclear architecture and genome stability and expression. Amongst the locations where heterochromatin is found, the pericentric regions have the capability to attract the histone variant macroH2A1. However, the factors and mechanisms behind macroH2A1 incorporation into these regions have not been explored. In this study, we probe different conditions that lead to the recruitment of macroH2A1 to pericentromeric regions and elucidate its underlying functions. Through experiments conducted on murine fibroblastic cells, we determine that partial chromatin relaxation resulting from DNA damage, senescence, or histone hyper-acetylation is necessary for the recruitment of macroH2A1 to pericentric regions. Furthermore, macroH2A1 is required for upregulation of noncoding pericentric RNA expression but not for pericentric chromatin organization. Our findings shed light on the functional rather than structural significance of macroH2A1 incorporation into pericentric chromatin.

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The histone variant macroH2A1.1 regulates RNA polymerase II-paused genes within defined chromatin interaction landscapes

Cited by 13 publications

References 90 publications

MacroH2A histone variants modulate enhancer activity to repress oncogenic programs and cellular reprogramming

MacroH2A histone variants modulate enhancer activity to repress oncogenic programs and cellular reprogramming

Deficiency of histone variant macroH2A1.1 is associated with sexually dimorphic obesity in mice

Recruitment of the Histone Variant MacroH2A1 to the Pericentric Region Occurs upon Chromatin Relaxation and Is Responsible for Major Satellite Transcriptional Regulation

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