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

Chen, Hongshan; Ruiz, Penelope D.; McKimpson, Wendy M.; Novikov, Leonid; Kitsis, Richard N.; Gamble, Matthew J.

doi:10.1016/j.molcel.2015.07.011

Cited by 189 publications

(184 citation statements)

References 62 publications

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“…Among SASP cytokines/chemokines, IL8 expression displayed a 2-fold increase in protein levels in cells transgenic for macroH2A1 isoforms upon 5-azadC treatment. macroH2A1 was recently shown as a critical component of the feedback loop that maintains SASP in oncogene-induced senescence (45). Our RNA-Seq showed that cells transgenic for macroH2A1 isoforms displayed higher levels of mRNAs involved in oncogenesis than cells depleted of macroH2A1.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

“…Conversely, macroH2A1 could be both a powerful tissue biomarker to stratify HCC patients (3) and a new target to implement SASP- and chemotherapy-based therapeutic opportunities (24, 38, 45). …”

Section: Discussionmentioning

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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“…In cellular senescence, proliferation becomes arrested and cells acquire a pro-inflammatory senescent secretory phenotype (SASP), with release of chemokines and cytokines [35]. We and others have shown that macroH2A1.1 ectopic expression sustains SASP in fibroblasts and hepatoma cells [12, 36]; a similar signaling loop might take place in the adipose tissue. How to boost macroH2A1.2 expression/activity, to the detriment of macroH2A1.1, with an anti-obesity therapeutic purpose?…”

Section: Discussionmentioning

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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“…The cell numbers were counted up to 8 days with a hemocytometer. Immunofluorescence was essentially performed as previously described 7 .…”

Section: Methodsmentioning

confidence: 99%

“…Chromatin Immunoprecipitation (ChIP) was performed as previously described 7 . A list of antibodies and primers used for ChIP-qPCR are listed in Tables S1 and S2.…”

Section: Methodsmentioning

confidence: 99%

A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression

et al. 2016

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Protein arginine methyltransferase 5 (PRMT5) complexed with MEP50/WDR77 catalyzes arginine methylation on histones and other proteins. PRMT5-MEP50 activity is elevated in cancer cells and its expression is highly correlated with poor prognosis in many human tumors. We demonstrate that PRMT5-MEP50 is essential for transcriptional regulation promoting cancer cell invasive phenotypes in lung adenocarcinoma, lung squamous cell carcinoma and breast carcinoma cancer cells. RNA-Seq transcriptome analysis demonstrated that PRMT5 and MEP50 are required to maintain expression of metastasis and Epithelial-to-mesenchymal transition (EMT) markers and to potentiate an epigenetic mechanism of the TGFβ response. We show that PRMT5-MEP50 activity both positively and negatively regulates expression of a wide range of genes. Exogenous TGFβ promotes EMT in a unique pathway of PRMT5-MEP50 catalyzed histone mono- and dimethylation of chromatin at key metastasis suppressor and EMT genes, defining a new mechanism regulating cancer invasivity. PRMT5 methylation of histone H3R2me1 induced transcriptional activation by recruitment of WDR5 and concomitant H3K4 methylation at targeted genes. In parallel, PRMT5 methylation of histone H4R3me2s suppressed transcription at distinct genomic loci. Our decoding of histone methylarginine at key genes supports a critical role for complementary PRMT5-MEP50 transcriptional activation and repression in cancer invasion pathways and in response to TGFβ stimulation and therefore and orients future chemotherapeutic opportunities.

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

Cited by 189 publications

References 62 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

A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression

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