Histone variants confer chromatin unique properties. They have specific genomic distribution, regulated by specific deposition and removal machineries. Histone variants, mostly of canonical histones H2A, H2B and H3, have important roles in early embryonic development, in lineage commitment of stem cells, in the converse process of somatic cell reprogramming to pluripotency and, in some cases, in the modulation of animal aging and life span. 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. Furthermore, macroH2A1 participates in the formation of senescence-associated heterochromatic foci (SAHF) in senescent cells, and multiple lines of evidence in genetically modified mice suggest that macroH2A1 integrates nutritional cues from the extracellular environment to transcriptional programs. Here, we review current molecular evidence based on next generation sequencing data, cell assays and in vivo models supporting different mechanisms that could mediate the function of macroH2A1 in health span and life span. We will further discuss context-dependent and isoform-specific functions. The aim of this review is to provide guidance to assess histone variant macroH2A1 potential as a therapeutic intervention point.

Center for Translational Medicine International Clinical Research Center St'Anne University Hospital Brno 656 91 Czech Republic

Division of Medicine Institute for Liver and Digestive Health University College London London WC1E 6BT UK

Faculty of Medicine Masaryk University Brno 656 91 Czech Republic

Zobrazit více v PubMed

Buschbeck M., Hake S.B. Variants of core histones and their roles in cell fate decisions, development and cancer. Nat. Rev. Mol. Cell Biol. 2017;18:299–314. doi: 10.1038/nrm.2016.166. PubMed DOI

Talbert P.B., Henikoff S. Histone variants—Ancient wrap artists of the epigenome. Nat. Rev. Mol. Cell Biol. 2010;11:264–275. doi: 10.1038/nrm2861. PubMed DOI

Talbert P.B., Henikoff S. Environmental responses mediated by histone variants. Trends Cell Biol. 2014;24:642–650. doi: 10.1016/j.tcb.2014.07.006. PubMed DOI

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

Filipescu D., Muller S., Almouzni G. Histone H3 variants and their chaperones during development and disease: Contributing to epigenetic control. Annu. Rev. Cell Dev. Biol. 2014;30:615–646. doi: 10.1146/annurev-cellbio-100913-013311. PubMed DOI

Gurard-Levin Z.A., Quivy J.P., Almouzni G. Histone chaperones: Assisting histone traffic and nucleosome dynamics. Annu. Rev. Biochem. 2014;83:487–517. doi: 10.1146/annurev-biochem-060713-035536. PubMed DOI

Rivera-Casas C., Gonzalez-Romero R., Cheema M.S., Ausio J., Eirin-Lopez J.M. The characterization of macroH2A beyond vertebrates supports an ancestral origin and conserved role for histone variants in chromatin. Epigenetics. 2016;11:415–425. doi: 10.1080/15592294.2016.1172161. PubMed DOI PMC

Rasmussen T.P., Huang T., Mastrangelo M.A., Loring J., Panning B., Jaenisch R. Messenger RNAs encoding mouse histone macroH2A1 isoforms are expressed at similar levels in male and female cells and result from alternative splicing. Nucleic Acids Res. 1999;27:3685–3689. doi: 10.1093/nar/27.18.3685. PubMed DOI PMC

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

Hernandez-Munoz I., Lund A.H., van der Stoop P., Boutsma E., Muijrers I., Verhoeven E., Nusinow D.A., Panning B., Marahrens Y., van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc. Natl. Acad. Sci. USA. 2005;102:7635–7640. doi: 10.1073/pnas.0408918102. PubMed DOI PMC

Nusinow D.A., Hernandez-Munoz I., Fazzio T.G., Shah G.M., Kraus W.L., Panning B. Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome. J. Biol. Chem. 2007;282:12851–12859. doi: 10.1074/jbc.M610502200. PubMed DOI

Mietton F., Sengupta A.K., Molla A., Picchi G., Barral S., Heliot L., Grange T., Wutz A., Dimitrov S. Weak but uniform enrichment of the histone variant macroH2A1 along the inactive X chromosome. Mol. Cell Biol. 2009;29:150–156. doi: 10.1128/MCB.00997-08. PubMed DOI PMC

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

Borghesan M., Fusilli C., Rappa F., Panebianco C., Rizzo G., Oben J.A., Mazzoccoli G., Faulkes C., Pata I., Agodi A. DNA Hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression. Cancer Res. 2016;76:594–606. doi: 10.1158/0008-5472.CAN-15-1336. PubMed DOI PMC

Pazienza V., Panebianco C., Rappa F., Memoli D., Borghesan M., Cannito S., Oji A., Mazza G., Tamburrino D., Fusai G. Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis. Epigenet. Chromat. 2016;9:45. doi: 10.1186/s13072-016-0098-9. PubMed DOI PMC

Creppe C., Janich P., Cantarino N., Noguera M., Valero V., Musulen E., Douet J., Posavec M., Martín-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;32:1442–1452. doi: 10.1128/MCB.06323-11. PubMed DOI PMC

Creppe C., Posavec M., Douet J., Buschbeck M. MacroH2A in stem cells: A story beyond gene repression. Epigenomics. 2012;4:221–227. doi: 10.2217/epi.12.8. PubMed DOI

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

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

Posavec M., Timinszky G., Buschbeck M. Macro domains as metabolite sensors on chromatin. Cell Mol. Life Sci. 2013;70:1509–1524. doi: 10.1007/s00018-013-1294-4. PubMed DOI PMC

Lo Re O., Fusilli C., Rappa F., Van Haele M., Douet J., Pindjakova J., Rocha S.W., Pata I., Valčíková B., Uldrijan S., et al. Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma. Hepatology. 2017 doi: 10.1002/hep.29519. PubMed DOI

Kapoor A., Goldberg M.S., Cumberland L.K., Ratnakumar K., Segura M.F., Emanuel P.O. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature. 2010;468:1105–1109. doi: 10.1038/nature09590. PubMed DOI PMC

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

Park S.J., Shim J.W., Park H.S., Eum D.Y., Park M.T., Mi Yi J., Choi S.H., Kim S.D., Son T.G., Lu W., et al. MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells by transactivation of Lin28B. Oncogene. 2016;35:1292–1301. doi: 10.1038/onc.2015.187. PubMed DOI PMC

Novikov L., Park J.W., Chen H., Klerman H., Jalloh A.S., Gamble M.J. QKI-mediated alternative splicing of the histone variant MacroH2A1 regulates cancer cell proliferation. Mol. Cell Biol. 2011;31:4244–4255. doi: 10.1128/MCB.05244-11. PubMed DOI PMC

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

Jueliger S., Lyons J., Cannito S., Pata I., Pata P., Shkolnaya M., Lo Re O., Peyrou M., Villarroya F., Pazienza V., et al. Efficacy and epigenetic interactions of novel DNA hypomethylating agent guadecitabine (SGI-110) in preclinical models of hepatocellular carcinoma. Epigenetics. 2016 doi: 10.1080/15592294.2016.1214781. Epub ahead of print. PubMed DOI PMC

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:e54458. doi: 10.1371/annotation/b456329c-02fa-4055-afb8-2090cec17da6. PubMed DOI PMC

Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115. doi: 10.1186/gb-2013-14-10-r115. PubMed DOI PMC

Lowe D., Horvath S., Raj K. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget. 2016;7:8524–8531. doi: 10.18632/oncotarget.7383. PubMed DOI PMC

Zhang R., Poustovoitov M.V., Ye X., Santos H.A., Chen W., Daganzo S.M., Erzberger J.P., Serebriiskii I.G., Canutescu A.A., Dunbrack R.L., et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell. 2005;8:19–30. doi: 10.1016/j.devcel.2004.10.019. PubMed DOI

Sulli G., Di Micco R., d’Adda di Fagagna F. Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer. Nat. Rev. Cancer. 2012;12:709–720. doi: 10.1038/nrc3344. PubMed DOI

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

Coppe J.P., Desprez P.Y., Krtolica A., Campisi J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu. Rev. Pathol. 2010;5:99–118. doi: 10.1146/annurev-pathol-121808-102144. PubMed DOI PMC

Kozlowski M., Ladurner A.G. ATM, MacroH2A.1, and SASP: The checks and balances of cellular senescence. Mol. Cell. 2015;59:713–715. doi: 10.1016/j.molcel.2015.08.010. PubMed DOI

Chen H., Ruiz P.D., McKimpson W.M., Novikov L., Kitsis R.N., Gamble M.J. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol. Cell. 2015;59:719–731. doi: 10.1016/j.molcel.2015.07.011. PubMed DOI PMC

Storer M., Mas A., Robert-Moreno A., Pecoraro M., Ortells M.C., Di Giacomo V., Yosef R., Pilpel N., Krizhanovsky V., Sharpe J., et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell. 2013;155:1119–1130. doi: 10.1016/j.cell.2013.10.041. PubMed DOI

Changolkar L.N., Costanzi C., Leu N.A., Chen D., McLaughlin K.J., Pehrson J.R. Developmental changes in histone macroH2A1-mediated gene regulation. Mol. Cell Biol. 2007;27:2758–2764. doi: 10.1128/MCB.02334-06. PubMed DOI PMC

Changolkar L.N., Singh G., Cui K., Berletch J.B., Zhao K., Disteche C.M., Pehrson J.R. Genome-wide distribution of macroH2A1 histone variants in mouse liver chromatin. Mol. Cell Biol. 2010;30:5473–5483. PubMed PMC

Buschbeck M., Uribesalgo I., Wibowo I., Rue P., Martin D., Gutierrez A., Morey L., Guigó R., López-Schier H., Di Croce L. The histone variant macroH2A is an epigenetic regulator of key developmental genes. Nat. Struct. Mol. Biol. 2009;16:1074–1079. doi: 10.1038/nsmb.1665. PubMed DOI

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

Pogribny I.P., Tryndyak V.P., Bagnyukova T.V., Melnyk S., Montgomery B., Ross S.A., Latendresse J.R., Rusyn I., Beland F.A. Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet. J. Hepatol. 2009;51:176–186. doi: 10.1016/j.jhep.2009.03.021. PubMed DOI PMC

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;6:35–47. doi: 10.18632/aging.100632. PubMed DOI PMC

Podrini C., Koffas A., Chokshi S., Vinciguerra M., Lelliott C.J., White J.K., Adissu H.A., Williams R., Greco A. MacroH2A1 isoforms are associated with epigenetic markers for activation of lipogenic genes in fat-induced steatosis. FASEB J. 2015;29:1676–1687. doi: 10.1096/fj.14-262717. PubMed DOI

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

Sheedfar F., Vermeer M., Pazienza V., Villarroya J., Rappa F., Cappello F., Mazzoccoli G., Villarroya F., van der Molen H., Hofker M.H., 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. 2015;39:331–338. doi: 10.1038/ijo.2014.91. PubMed DOI

Marjanovic M.P., Hurtado-Bages S., Lassi M., Valero V., Malinverni R., Delage H., Navarro M., Corujo D., Guberovic I., Douet J., et al. MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption. Nat. Struct. Mol. Biol. 2017 doi: 10.1038/nsmb.3481. PubMed DOI PMC

Dell’Orso S., Wang A.H., Shih H.Y., Saso K., Berghella L., Gutierrez-Cruz G., Ladurner A.G., O’Shea J.J., Sartorelli V., Zare H. The histone variant MacroH2A1.2 is necessary for the activation of muscle enhancers and recruitment of the transcription factor Pbx1. Cell Rep. 2016;14:1156–1168. doi: 10.1016/j.celrep.2015.12.103. PubMed DOI PMC

Wan D., Liu C., Sun Y., Wang W., Huang K., Zheng L. MacroH2A1.1 cooperates with EZH2 to promote adipogenesis by regulating Wnt signaling. J. Mol. Cell Biol. 2017;9:325–337. doi: 10.1093/jmcb/mjx027. PubMed DOI

Brandhorst S., Choi I.Y., Wei M., Cheng C.W., Sedrakyan S., Navarrete G., Dubeau L., Yap L.P., Park R., Vinciguerra M., et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 2015;22:86–99. doi: 10.1016/j.cmet.2015.05.012. PubMed DOI PMC

Di Biase S., Longo V.D. Fasting-induced differential stress sensitization in cancer treatment. Mol. Cell Oncol. 2016;3:e1117701. doi: 10.1080/23723556.2015.1117701. PubMed DOI PMC

Cheng C.W., Adams G.B., Perin L., Wei M., Zhou X., Lam B.S., Da Sacco S., Mirisola M., Quinn D.I., Dorff T.B., et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14:810–823. doi: 10.1016/j.stem.2014.04.014. PubMed DOI PMC

Pehrson J.R., Changolkar L.N., Costanzi C., Leu N.A. Mice without macroH2A histone variants. Mol. Cell Biol. 2014;34:4523–4533. doi: 10.1128/MCB.00794-14. PubMed DOI PMC

Pasque V., Jullien J., Miyamoto K., Halley-Stott R.P., Gurdon J.B. Epigenetic factors influencing resistance to nuclear reprogramming. Trends Genet. 2011;27:516–525. doi: 10.1016/j.tig.2011.08.002. PubMed DOI PMC

Chang C.C., Gao S., Sung L.Y., Corry G.N., Ma Y., Nagy Z.P., Tian X.C., Rasmussen T.P. Rapid elimination of the histone variant MacroH2A from somatic cell heterochromatin after nuclear transfer. Cell Reprogram. 2010;12:43–53. doi: 10.1089/cell.2009.0043. PubMed DOI PMC

Pasque V., Radzisheuskaya A., Gillich A., Halley-Stott R.P., Panamarova M., Zernicka-Goetz M., Surani M.A., Silva J.C. Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. (Pt 24)J. Cell Sci. 2012;125:6094–6104. doi: 10.1242/jcs.113019. PubMed DOI PMC

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

Barrero M.J., Sese B., Marti M., Izpisua Belmonte J.C. Macro histone variants are critical for the differentiation of human pluripotent cells. J. Biol. Chem. 2013;288:16110–16116. doi: 10.1074/jbc.M113.466144. PubMed DOI PMC

Gaspar-Maia A., Qadeer Z.A., Hasson D., Ratnakumar K., Leu N.A., 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

Fu Y., Lv P., Yan G., Fan H., Cheng L., Zhang F., Dang Y., Wu H., Wen B. MacroH2A1 associates with nuclear lamina and maintains chromatin architecture in mouse liver cells. Sci. Rep. 2015;5:17186. doi: 10.1038/srep17186. PubMed DOI PMC

Douet J., Corujo D., Malinverni R., Renauld J., Sansoni V., Marjanovic M.P., Cantari’o N., Valero V., Mongelard F., Bouvet P., et al. MacroH2A histone variants maintain nuclear organization and heterochromatin architecture. J. Cell Sci. 2017 doi: 10.1242/jcs.199216. PubMed DOI

Angelov D., Molla A., Perche P.Y., Hans F., Cote J., Khochbin S., Bouvet P., Dimitrov S. The histone variant macroH2A interferes with transcription factor binding and SWI/SNF nucleosome remodeling. Mol. Cell. 2003;11:1033–1041. doi: 10.1016/S1097-2765(03)00100-X. PubMed DOI

Ratnakumar K., Duarte L.F., LeRoy G., Hasson D., Smeets D., Vardabasso C., Bonisch C., Zeng T., Xiang B., Zhang D.Y., et al. ATRX-mediated chromatin association of histone variant macroH2A1 regulates alpha-globin expression. Genes Dev. 2012;26:433–438. doi: 10.1101/gad.179416.111. PubMed DOI PMC

Mehrotra P.V., Ahel D., Ryan D.P., Weston R., Wiechens N., Kraehenbuehl R., Owen-Hughes T., Ahel I. DNA repair factor APLF is a histone chaperone. Mol. Cell. 2011;41:46–55. doi: 10.1016/j.molcel.2010.12.008. PubMed DOI PMC

Hussey K.M., Chen H., Yang C., Park E., Hah N., Erdjument-Bromage H., Tempst P., Gamble M.J., Kraus W.L. The histone variant MacroH2A1 regulates target gene expression in part by recruiting the transcriptional coregulator PELP1. Mol. Cell Biol. 2014;34:2437–2449. doi: 10.1128/MCB.01315-13. PubMed DOI PMC

Chen H., Ruiz P.D., Novikov L., Casill A.D., Park J.W., Gamble M.J. MacroH2A1.1 and PARP-1 cooperate to regulate transcription by promoting CBP-mediated H2B acetylation. Nat. Struct. Mol. Biol. 2014;21:981–989. doi: 10.1038/nsmb.2903. PubMed DOI PMC

Jufvas A., Stralfors P., Vener A.V. Histone variants and their post-translational modifications in primary human fat cells. PLoS ONE. 2011;6:e15960. doi: 10.1371/journal.pone.0015960. PubMed DOI PMC

Chu F., Nusinow D.A., Chalkley R.J., Plath K., Panning B., Burlingame A.L. Mapping post-translational modifications of the histone variant MacroH2A1 using tandem mass spectrometry. Mol. Cell Proteom. 2006;5:194–203. doi: 10.1074/mcp.M500285-MCP200. PubMed DOI

Bernstein E., Muratore-Schroeder T.L., Diaz R.L., Chow J.C., Changolkar L.N., Shabanowitz J., Heard E., Pehrson J.R., Hunt D.F., Allis C.D. A phosphorylated subpopulation of the histone variant macroH2A1 is excluded from the inactive X chromosome and enriched during mitosis. Proc. Natl. Acad. Sci. USA. 2008;105:1533–1538. doi: 10.1073/pnas.0711632105. PubMed DOI PMC

Timinszky G., Till S., Hassa P.O., Hothorn M., Kustatscher G., Nijmeijer B., Colombelli J., Altmeyer M., Stelzer E.H., Scheffzek K., et al. A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nat. Struct. Mol. Biol. 2009;16:923–929. doi: 10.1038/nsmb.1664. PubMed DOI

Sellou H., Lebeaupin T., Chapuis C., Smith R., Hegele A., Singh H.R., Kozlowski M., Bultmann S., Ladurner A.G., Timinszky G., et al. The poly(ADP-ribose)-dependent chromatin remodeler Alc1 induces local chromatin relaxation upon DNA damage. Mol. Biol. Cell. 2016;27:3791–3799. doi: 10.1091/mbc.E16-05-0269. PubMed DOI PMC

Natoli G. Control of NF-κB-dependent transcriptional responses by chromatin organization. Cold Spring Harb. Perspect. Biol. 2009;1:a000224. doi: 10.1101/cshperspect.a000224. PubMed DOI PMC

Takase O., Yoshikawa M., Idei M., Hirahashi J., Fujita T., Takato T., Isagawa T., Nagae G., Suemori H., Aburatani H., et al. The role of NF-κB signaling in the maintenance of pluripotency of human induced pluripotent stem cells. PLoS ONE. 2013;8:e56399. doi: 10.1371/journal.pone.0056399. PubMed DOI PMC

Michael S., Achilleos C., Panayiotou T., Strati K. Inflammation shapes stem cells and stemness during infection and beyond. Front. Cell Dev. Biol. 2016;4:118. doi: 10.3389/fcell.2016.00118. PubMed DOI PMC

Shigdar S., Li Y., Bhattacharya S., O’Connor M., Pu C., Lin J., Wang T., Xiang D., Kong L., Wei M.Q., et al. Inflammation and cancer stem cells. Cancer Lett. 2014;345:271–278. doi: 10.1016/j.canlet.2013.07.031. PubMed DOI

Arany P.R., Cho A., Hunt T.D., Sidhu G., Shin K., Hahm E., Huang G.X., Weaver J., Chen A.C., Padwa B.L., et al. Photoactivation of endogenous latent transforming growth factor-β1 directs dental stem cell differentiation for regeneration. Sci. Transl. Med. 2014;6:238ra69. doi: 10.1126/scitranslmed.3008234. PubMed DOI PMC

Jiang B.H., Chen W.Y., Li H.Y., Chien Y., Chang W.C., Hsieh P.C., Wu P., Chen C.Y., Song H.Y., Chien C.S., et al. CHD1L Regulated PARP1-driven pluripotency and chromatin remodeling during the early-stage cell reprogramming. Stem Cells. 2015;33:2961–2972. doi: 10.1002/stem.2116. PubMed DOI PMC

Ouararhni K., Hadj-Slimane R., Ait-Si-Ali S., Robin P., Mietton F., Harel-Bellan A., Dimitrov S., Hamiche A. The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. Genes Dev. 2006;20:3324–3336. doi: 10.1101/gad.396106. PubMed DOI PMC

Ladurner A., Sporn J., Muley T. Diagnostic Method for Predicting the Risk of Cancer Recurrence Based on Histone MacroH2A Isoforms. CA2766656 A1. Google Patents. 2010 Januray;

Hamiche A. MacroH2A Non-Histone Domain as Inhibitor of PARP-1 Activity and Uses Thereof. EP1948215 B1. Google Patents. 2012 Jan 11;

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

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

Phosphorylation within Intrinsic Disordered Region Discriminates Histone Variant macroH2A1 Splicing Isoforms-macroH2A1.1 and macroH2A1.2

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 macroH2A1 decreases mitochondrial metabolism and reduces the aggressiveness of uveal melanoma cells

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

A Role for the Biological Clock in Liver Cancer

Deficiency and haploinsufficiency of histone macroH2A1.1 in mice recapitulate hematopoietic defects of human myelodysplastic syndrome

Macro Histone Variants: Emerging Rheostats of Gastrointestinal Cancers

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