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

Sheedfar, Fareeba; Vermeer, Marloes; Pazienza, Valerio; Villarroya, Joan; Rappa, Francesca; Cappello, Francesco; Mazzoccoli, Gianluigi; Villarroya, Francesc; Molen, Henk van der; Hofker, Marten H.; Koonen, Debby P. Y.; Vinciguerra, Manlio

doi:10.1038/ijo.2014.91

Cited by 21 publications

(27 citation statements)

References 51 publications

(67 reference statements)

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“…We used whole-body KO mice for macroH2A1 (12) to investigate age-dependent hepatocyte senescence and DNA methylation. We stained the livers of 21.4- to 23.3-month-old macroH2A1 KO mice and aged-matched wild-type littermates for senescence-associated X-gal staining.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…In the liver, genome binding and transcriptomic studies using knock-out (KO) mice have shown that macroH2A1 participates in the pathogenesis of NAFLD and fat-induced obesity (12–18). Moreover, increased expression of macroH2A1 isoforms in the liver might be used as a diagnostic and prognostic marker for HCC (3).…”

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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“…3c, upper panels). Similarly, when fed an obesogenic (12 weeks, 60% energy from lard [22]) high fat (HF) diet, macroH2A1.2 Tg mice appeared leaner and protected from fat induced-increased adiposity to the naked eye (Fig. 3c, lower panels).…”

Section: Resultsmentioning

confidence: 99%

“…Mice models, knockout (KO) for the whole macroH2A1 gene, have been reported. In KO mice generated in the pure C57BL/6 J background, modest developmental changes in macroH2A1-mediated gene regulation under a standard diet, and a very mild systemic protection against obesity upon a high fat regimen, were observed [21, 22]. By contrast, in KO mice for macroH2A1 generated in a mixed background a variable hepatic lipid accumulation in 50% of the females has been described, without changes in body weight [23].…”

Section: Introductionmentioning

confidence: 99%

Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis

Pazienza

Panebianco

Rappa

et al. 2016

Epigenetics & Chromatin

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BackgroundObesity has tremendous impact on the health systems. Its epigenetic bases are unclear. MacroH2A1 is a variant of histone H2A, present in two alternatively exon-spliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Their role in adipose tissue plasticity is unknown.ResultsHere, we show evidence that macroH2A1.1 protein levels in the visceral adipose tissue of obese humans positively correlate with BMI, while macroH2A1.2 is nearly absent. We thus introduced a constitutive GFP-tagged transgene for macroH2A1.2 in mice, and we characterized their metabolic health upon being fed a standard chow diet or a high fat diet. Despite unchanged food intake, these mice exhibit lower adipose mass and improved glucose metabolism both under a chow and an obesogenic diet. In the latter regimen, transgenic mice display smaller pancreatic islets and significantly less inflammation. MacroH2A1.2 overexpression in the mouse adipose tissue induced dramatic changes in the transcript levels of key adipogenic genes; genomic analyses comparing pre-adipocytes to mature adipocytes uncovered only minor changes in macroH2A1.2 genomic distribution upon adipogenic differentiation and suggested differential cooperation with transcription factors. MacroH2A1.2 overexpression markedly inhibited adipogenesis, while overexpression of macroH2A1.1 had opposite effects.ConclusionsMacroH2A1.2 is an unprecedented chromatin component powerfully promoting metabolic health by modulating anti-adipogenic transcriptional networks in the differentiating adipose tissue. Strategies aiming at enhancing macroH2A1.2 expression might counteract excessive adiposity in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0098-9) contains supplementary material, which is available to authorized users.

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“…Histone variants, as well as modifications, can be associated with disease. Over-or underexpression, mutations and defective splice variants of H2A variants and the variant H3.3 have been associated with many different human cancers and are potential biomarkers and therapeutic targets [190,191] and macroH2A1 knock-out can protect against diet-induced obesity in mice [192]. In paper I we identified several histone variants in mature, primary human adipocytes, some of these had never been identified on protein level before and some had been considered to be oocyte or testis specific.…”

Section: Histone Variantsmentioning

confidence: 96%

Human Adipocytes : Proteomic Approaches

Jufvas¹

2016

Linköping University Medical Dissertations

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Type 2 diabetes is characterized by increased levels of glucose in the blood originating from insulin resistance in insulin sensitive tissues and from reduced pancreatic insulin production. Around 400 million people in the world are diagnosed with type 2 diabetes and the correlation with obesity is strong. In addition to life style induction of obesity and type 2 diabetes, there are indications of genetic and epigenetic influences. This thesis has focused on the characterization of primary human adipocytes, who play a crucial role in the development of type 2 diabetes. Histones are important proteins in chromatin dynamics and may be one of the factors behind epigenetic inheritance. In paper I, we characterized histone variants and posttranslational modifications in human adipocytes. Several of the specific posttranslational histone modifications we identified have been characterized in other cell types, but the majority was not previously known. Moreover, we identified a variant of histone H4 on protein level for the first time. In paper II, we studied specific histone H3 methylations in the adipocytes. We found that overweight is correlated with a reduction of H3K4me2 while type 2 diabetes is associated with an increase of H3K4me3. This shows a genome-wide difference in important chromatin modifications that could help explain the epidemiologically shown association between epigenetics and metabolic health. Caveolae is a plasma membrane structure involved in the initial and important steps of insulin signaling. In paper III we characterized the IQGAP1 interactome in human adipocytes and suggest that IQGAP1 is a link between caveolae and the cytoskeleton. Moreover, the amount of IQGAP1 is drastically lower in adipocytes from type 2 diabetic subjects compared with controls implying a potential role for IQGAP1 in insulin resistance. In conclusion, this thesis provides new insights into the insulin signaling frameworks and the histone variants and modifications of human adipocytes

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

Abstract: Genetic eviction of macroH2A1 confers protection against diet-induced obesity and metabolic derangements in mice. Inhibition of macroH2A1 might be a helpful strategy for epigenetic therapy of obesity.

Cited by 21 publications

References 51 publications

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

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

Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis

Human Adipocytes : Proteomic Approaches

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