BACKGROUND: Obesity 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. RESULTS: Here, 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. CONCLUSIONS: MacroH2A1.2 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.

Centre for HPB Surgery and Liver Transplantation Royal Free Hospital London NW3 2QG UK

Departament de Bioquimica i Biologia Molecular Institut de Biomedicina de la Universitat de Barcelona ISCIII Madrid Spain

Department of Experimental Biomedicine and Clinical Neurosciences Section of Human Anatomy University of Palermo 90127 Palermo Italy ; Department of Legal Society and Sport Sciences University of Palermo 90133 Palermo Italy ; Euro Mediterranean Institute of Science and Technology 90146 Palermo Italy

Department of Experimental Biomedicine and Clinical Neurosciences Section of Human Anatomy University of Palermo 90127 Palermo Italy ; Euro Mediterranean Institute of Science and Technology 90146 Palermo Italy

Faculty of Medicine Tottori University Yonago 683 8503 Japan

Faculty of Medicine Tottori University Yonago 683 8503 Japan ; The Institute of Medical Sciences University of Tokyo Tokyo 108 8639 Japan

Gastroenterology Unit IRCCS Casa Sollievo della Sofferenza Hospital 71013 San Giovanni Rotondo Italy

Gastroenterology Unit IRCCS Casa Sollievo della Sofferenza Hospital 71013 San Giovanni Rotondo Italy ; Euro Mediterranean Institute of Science and Technology St Anne's University Hospital Brno 656 91 Czech Republic

Gastroenterology Unit IRCCS Casa Sollievo della Sofferenza Hospital 71013 San Giovanni Rotondo Italy ; Institute for Liver and Digestive Health University College London Royal Free Hospital London NW3 2PF UK

Institute for Liver and Digestive Health University College London Royal Free Hospital London NW3 2PF UK

Laboratory of Molecular Medicine and Genomics Department of Medicine Surgery and Dentistry 'Schola Medica Salernitana' University of Salerno 84081 Baronissi SA Italy

Mouse Biology Unit European Molecular Biology Laboratory 00015 Monterotondo Italy

Research Institute for Microbial Diseases Osaka University Suita Osaka 5650871 Japan

Zobrazit více v PubMed

Podrini C, Borghesan M, Greco A, Pazienza V, Mazzoccoli G, Vinciguerra M. Redox homeostasis and epigenetics in non-alcoholic fatty liver disease (NAFLD) Curr Pharm Des. 2013;19(15):2737–2746. doi: 10.2174/1381612811319150009. PubMed DOI

Goni L, Milagro FI, Cuervo M, Martinez JA. Single-nucleotide polymorphisms and DNA methylation markers associated with central obesity and regulation of body weight. Nutr Rev. 2014;72(11):673–690. doi: 10.1111/nure.12143. PubMed DOI

Martinez JA, Milagro FI, Claycombe KJ, Schalinske KL. Epigenetics in adipose tissue, obesity, weight loss, and diabetes. Adv Nutr. 2014;5(1):71–81. doi: 10.3945/an.113.004705. PubMed DOI PMC

Dick KJ, Nelson CP, Tsaprouni L, Sandling JK, Aissi D, Wahl S, Meduri E, Morange PE, Gagnon F, Grallert H, et al. DNA methylation and body-mass index: a genome-wide analysis. Lancet. 2014;383(9933):1990–1998. doi: 10.1016/S0140-6736(13)62674-4. PubMed DOI

Henikoff S, Smith MM. Histone variants and epigenetics. Cold Spring Harb Perspect Biol. 2015;7(1):a019364. doi: 10.1101/cshperspect.a019364. PubMed DOI PMC

Skene PJ, Henikoff S. Histone variants in pluripotency and disease. Development. 2013;140(12):2513–2524. doi: 10.1242/dev.091439. PubMed DOI

Talbert PB, Henikoff S. Histone variants–ancient wrap artists of the epigenome. Nat Rev Mol Cell Biol. 2010;11(4):264–275. doi: 10.1038/nrm2861. PubMed DOI

Doyen CM, An W, Angelov D, Bondarenko V, Mietton F, Studitsky VM, Hamiche A, Roeder RG, Bouvet P, Dimitrov S. Mechanism of polymerase II transcription repression by the histone variant macroH2A. Mol Cell Biol. 2006;26(3):1156–1164. doi: 10.1128/MCB.26.3.1156-1164.2006. PubMed DOI PMC

Borghesan M, Mazzoccoli G, Sheedfar F, Oben J, Pazienza V, Vinciguerra M. Histone variants and lipid metabolism. Biochem Soc Trans. 2014;42(5):1409–1413. doi: 10.1042/BST20140119. PubMed DOI

Pazienza V, Borghesan M, Mazza T, Sheedfar F, Panebianco C, Williams R, Mazzoccoli G, Andriulli A, Nakanishi T, Vinciguerra M. SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation. Aging. 2014;6(1):35–47. doi: 10.18632/aging.100632. PubMed DOI PMC

Gamble MJ, Frizzell KM, Yang C, Krishnakumar R, Kraus WL. The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing. Genes Dev. 2010;24(1):21–32. doi: 10.1101/gad.1876110. PubMed DOI PMC

Borghesan M, Fusilli C, Rappa F, Panebianco C, Rizzo G, Oben JA, Mazzoccoli G, Faulkes C, Pata I, Agodi A, Rezaee F, Minogue S, Warren A, Peterson A, Sedivy JM, Douet J, Buschbeck M, Cappello F, Mazza T, Pazienza V, Vinciguerra M. DNA hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression. Cancer Res. 2016;76(3):594–606. doi: 10.1158/0008-5472.CAN-15-1336. PubMed DOI PMC

Jueliger S, Lyons J, Cannito S, Pata I, Pata P, Shkolnaya M, Lo Re O, Peyrou M, Villarroya F, Pazienza V, Rappa F, Cappello F, Azab M, Taverna P, Vinciguerra M: Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma. Epigenetics Published online: 11 Aug 2016. doi: 10.1080/15592294.2016.1214781. PubMed PMC

Creppe C, Janich P, Cantarino N, Noguera M, Valero V, Musulen E, Douet J, Posavec M, Martin-Caballero J, Sumoy L, et al. MacroH2A1 regulates the balance between self-renewal and differentiation commitment in embryonic and adult stem cells. Mol Cell Biol. 2012;32(8):1442–1452. doi: 10.1128/MCB.06323-11. PubMed DOI PMC

Cantarino N, Douet J, Buschbeck M. MacroH2A–an epigenetic regulator of cancer. Cancer Lett. 2013;336(2):247–252. doi: 10.1016/j.canlet.2013.03.022. PubMed DOI

Barrero MJ, Sese B, Kuebler B, Bilic J, Boue S, Marti M, Izpisua Belmonte JC. Macrohistone variants preserve cell identity by preventing the gain of H3K4me2 during reprogramming to pluripotency. Cell Rep. 2013;3(4):1005–1011. doi: 10.1016/j.celrep.2013.02.029. PubMed DOI

Gaspar-Maia A, Qadeer ZA, Hasson D, Ratnakumar K, Leu NA, Leroy G, Liu S, Costanzi C, Valle-Garcia D, Schaniel C, et al. MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. Nat Commun. 2013;4:1565. doi: 10.1038/ncomms2582. PubMed DOI PMC

Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner AG. Splicing regulates NAD metabolite binding to histone macroH2A. Nat Struct Mol Biol. 2005;12(7):624–625. doi: 10.1038/nsmb956. PubMed DOI

Sporn JC, Jung B. Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer. Am J Pathol. 2012;180(6):2516–2526. doi: 10.1016/j.ajpath.2012.02.027. PubMed DOI PMC

Sporn JC, Kustatscher G, Hothorn T, Collado M, Serrano M, Muley T, Schnabel P, Ladurner AG. Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene. 2009;28(38):3423–3428. doi: 10.1038/onc.2009.26. PubMed DOI

Changolkar LN, Costanzi C, Leu NA, Chen D, McLaughlin KJ, Pehrson JR. Developmental changes in histone macroH2A1-mediated gene regulation. Mol Cell Biol. 2007;27(7):2758–2764. doi: 10.1128/MCB.02334-06. PubMed DOI PMC

Sheedfar F, Vermeer M, Pazienza V, Villarroya J, Rappa F, Cappello F, Mazzoccoli G, Villarroya F, van der Molen H, Hofker MH, et al. Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet. Int J Obes (Lond) 2015;39(2):331–338. doi: 10.1038/ijo.2014.91. PubMed DOI

Boulard M, Storck S, Cong R, Pinto R, Delage H, Bouvet P. Histone variant macroH2A1 deletion in mice causes female-specific steatosis. Epigenetics Chromatin. 2010;3(1):8. doi: 10.1186/1756-8935-3-8. PubMed DOI PMC

Lin X, Yue P, Chen Z, Schonfeld G. Hepatic triglyceride contents are genetically determined in mice: results of a strain survey. Am J Physiol Gastrointest Liver Physiol. 2005;288(6):G1179–G1189. doi: 10.1152/ajpgi.00411.2004. PubMed DOI

Rappa F, Greco A, Podrini C, Cappello F, Foti M, Bourgoin L, Peyrou M, Marino A, Scibetta N, Williams R, et al. Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma. PLoS ONE. 2013;8(1):e54458. doi: 10.1371/journal.pone.0054458. PubMed DOI PMC

Soma A, Sato K, Nakanishi T. Visualization of inactive X chromosome in preimplantation embryos utilizing MacroH2A-EGFP transgenic mouse. Genesis. 2013;51(4):259–267. doi: 10.1002/dvg.22369. PubMed DOI

Carter R, Mouralidarane A, Soeda J, Ray S, Pombo J, Saraswati R, Novelli M, Fusai G, Rappa F, Saracino C, et al. Non-alcoholic fatty pancreas disease pathogenesis: a role for developmental programming and altered circadian rhythms. PLoS ONE. 2014;9(3):e89505. doi: 10.1371/journal.pone.0089505. PubMed DOI PMC

Arsenijevic T, Gregoire F, Delforge V, Delporte C, Perret J. Murine 3T3-L1 adipocyte cell differentiation model: validated reference genes for qPCR gene expression analysis. PLoS ONE. 2012;7(5):e37517. doi: 10.1371/journal.pone.0037517. PubMed DOI PMC

Fontana L, Vinciguerra M, Longo VD. Growth factors, nutrient signaling, and cardiovascular aging. Circ Res. 2012;110(8):1139–1150. doi: 10.1161/CIRCRESAHA.111.246470. PubMed DOI PMC

Gao X, Yan D, Zhao Y, Tao H, Zhou Y. Moderate calorie restriction to achieve normal weight reverses beta-cell dysfunction in diet-induced obese mice: involvement of autophagy. Nutr Metab (Lond) 2015;12:34. doi: 10.1186/s12986-015-0028-z. PubMed DOI PMC

Sakamoto H, Kogo Y, Ohgane J, Hattori N, Yagi S, Tanaka S, Shiota K. Sequential changes in genome-wide DNA methylation status during adipocyte differentiation. Biochem Biophys Res Commun. 2008;366(2):360–366. doi: 10.1016/j.bbrc.2007.11.137. PubMed DOI

Changolkar LN, Singh G, Cui K, Berletch JB, Zhao K, Disteche CM, Pehrson JR. Genome-wide distribution of macroH2A1 histone variants in mouse liver chromatin. Mol Cell Biol. 2010;30(23):5473–5483. doi: 10.1128/MCB.00518-10. PubMed DOI PMC

Molchadsky A, Ezra O, Amendola PG, Krantz D, Kogan-Sakin I, Buganim Y, Rivlin N, Goldfinger N, Folgiero V, Falcioni R, et al. p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity. Cell Death Differ. 2013;20(5):774–783. doi: 10.1038/cdd.2013.9. PubMed DOI PMC

Ji S, Doumit ME, Hill RA. Regulation of adipogenesis and key adipogenic gene expression by 1, 25-dihydroxyvitamin D in 3T3-L1 cells. PLoS ONE. 2015;10(6):e0126142. doi: 10.1371/journal.pone.0126142. PubMed DOI PMC

Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence. Aging Cell. 2010;9(5):667–684. doi: 10.1111/j.1474-9726.2010.00608.x. PubMed DOI PMC

Chen H, Ruiz PD, McKimpson WM, Novikov L, Kitsis RN, Gamble MJ. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol Cell. 2015;59(5):719–731. doi: 10.1016/j.molcel.2015.07.011. PubMed DOI PMC

Novikov L, Park JW, Chen H, Klerman H, Jalloh AS, Gamble MJ. QKI-mediated alternative splicing of the histone variant MacroH2A1 regulates cancer cell proliferation. Mol Cell Biol. 2011;31(20):4244–4255. doi: 10.1128/MCB.05244-11. PubMed DOI PMC

Dardenne E, Pierredon S, Driouch K, Gratadou L, Lacroix-Triki M, Espinoza MP, Zonta E, Germann S, Mortada H, Villemin JP, et al. Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness. Nat Struct Mol Biol. 2012;19(11):1139–1146. doi: 10.1038/nsmb.2390. PubMed DOI

Mazza G, Rombouts K, Rennie Hall A, Urbani L, Vinh Luong T, Al-Akkad W, Longato L, Brown D, Maghsoudlou P, Dhillon AP, et al. Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation. Sci Rep. 2015;5:13079. doi: 10.1038/srep13079. PubMed DOI PMC

Veyrat-Durebex C, Montet X, Vinciguerra M, Gjinovci A, Meda P, Foti M, Rohner-Jeanrenaud F. The Lou/C rat: a model of spontaneous food restriction associated with improved insulin sensitivity and decreased lipid storage in adipose tissue. Am J Physiol Endocrinol Metab. 2009;296(5):E1120–E1132. doi: 10.1152/ajpendo.90592.2008. PubMed DOI

Bolasco G, Calogero R, Carrara M, Banchaabouchi MA, Bilbao D, Mazzoccoli G, Vinciguerra M. Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice. Aging (Albany NY) 2012;4(6):402–416. doi: 10.18632/aging.100464. PubMed DOI PMC

Hintze JL, Nelson RD. Violin plots: a box plot-density trace synergism. Am Stat. 1998;52(2):181–184.

Xu S, Grullon S, Ge K, Peng W. Spatial clustering for identification of ChIP-enriched regions (SICER) to map regions of histone methylation patterns in embryonic stem cells. Methods Mol Biol. 2014;1150:97–111. doi: 10.1007/978-1-4939-0512-6_5. PubMed DOI PMC

Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38(4):576–589. doi: 10.1016/j.molcel.2010.05.004. PubMed DOI PMC

Zambelli F, Pesole G, Pavesi G: PscanChIP: finding over-represented transcription factor-binding site motifs and their correlations in sequences from ChIP-Seq experiments. Nucleic Acids Res 2013, 41(Web Server issue):W535–543. PubMed PMC

Chen TW, Li HP, Lee CC, Gan RC, Huang PJ, Wu TH, Lee CY, Chang YF, Tang P. ChIPseek, a web-based analysis tool for ChIP data. BMC Genom. 2014;15:539. doi: 10.1186/1471-2164-15-539. PubMed DOI PMC

Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D, Jones SJ, Marra MA. Circos: an information aesthetic for comparative genomics. Genome Res. 2009;19(9):1639–1645. doi: 10.1101/gr.092759.109. PubMed DOI PMC

Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–1321. doi: 10.1002/hep.20701. PubMed DOI

Mathur A, Marine M, Lu D, Swartz-Basile DA, Saxena R, Zyromski NJ, Pitt HA. Nonalcoholic fatty pancreas disease. HPB (Oxford) 2007;9(4):312–318. doi: 10.1080/13651820701504157. PubMed DOI PMC

Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant

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

GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/β-catenin and ALK5/SMAD2/3 pathways

Histone Variant macroH2A1.1 Enhances Nonhomologous End Joining-dependent DNA Double-strand-break Repair and Reprogramming Efficiency of Human iPSCs

Circulating histone signature of human lean metabolic-associated fatty liver disease (MAFLD)

Senescence-like phenotype in post-mitotic cells of mice entering middle age

Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Macro Histone Variants: Emerging Rheostats of Gastrointestinal Cancers

Mono-ADP-Ribosylhydrolase MACROD2 Is Dispensable for Murine Responses to Metabolic and Genotoxic Insults

Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells

Histone MacroH2A1: A Chromatin Point of Intersection between Fasting, Senescence and Cellular Regeneration

Developmental Programming of Obesity and Liver Metabolism by Maternal Perinatal Nutrition Involves the Melanocortin System

Gut Dysbiosis and Adaptive Immune Response in Diet-induced Obesity vs. Systemic Inflammation