[en] One of the most striking epigenetic alterations that occurs at the level of the nucleosome is the complete exchange of the canonical H2A histones for the macroH2A variant. Here, we provide insight into the poorly recognized function of macroH2A in transcriptional activation and demonstrate its relevance in embryonic and adult stem cells. Knockdown of macroH2A1 in mouse embryonic stem (mES) cells limited their capacity to differentiate but not their self-renewal. The loss of macroH2A1 interfered with the proper activation of differentiation genes, most of which are direct target genes of macroH2A. Additionally, macroH2A1-deficient mES cells displayed incomplete inactivation of pluripotency genes and formed defective embryoid bodies. In vivo, macroH2A1-deficient teratomas contained a massive expansion of malignant, undifferentiated carcinoma tissue. In the heterogeneous culture of primary human keratinocytes, macroH2A1 levels negatively correlated with the self-renewal capacity of the pluripotent compartment. Together these results establish macroH2A1 as a critical chromatin component that regulates the delicate balance between self-renewal and differentiation of embryonic and adult stem cells.
Agelopoulos M, Thanos D. 2006. Epigenetic determination of a cellspecific gene expression program by ATF-2 and the histone variant macroH2A. EMBO J. 25:4843-4853.
Barde I, Salmon P, Trono D. 2010. Production and titration of lentiviral vectors. Curr. Protoc. Neurosci. 53:4.21.1-4.21.23.
Barrandon Y, Green H. 1987. Three clonal types of keratinocyte with different capacities for multiplication. Proc. Natl. Acad. Sci. U. S. A. 84: 2302-2306.
Blum B, Bar-Nur O, Golan-Lev T, Benvenisty N. 2009. The antiapoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nat. Biotechnol. 27:281-287.
Boix R, et al. 2009. Primary renal cell carcinoma in a transplanted kidney: genetic evidence of recipient origin. Transplantation 87:1057-1061.
Boulard M, et al. 2010. Histone variant macroH2A1 deletion in mice causes female-specific steatosis. Epigenetics Chromatin. 3:8.
Buschbeck M, Di Croce L. 2010. Approaching the molecular and physiological function of macroH2A variants. Epigenetics 5:118-123.
Buschbeck M, Hofbauer S, Croce LD, Keri G, Ullrich A. 2005. Ablkinase-sensitive levels of ERK5 and its intrinsic basal activity contribute to leukaemia cell survival. EMBO Rep. 6:63-69.
Buschbeck M, et al. 2007. PML4 induces differentiation by Myc destabilization. Oncogene 26:3415-3422.
Buschbeck M, et al. 2009. The histone variant macroH2A is an epigenetic regulator of key developmental genes. Nat. Struct. Mol. Biol. 16:1074-1079.
Chakravarthy S, et al. 2005. Structural characterization of the histone variant macroH2A. Mol. Cell. Biol. 25:7616-7624.
Changolkar LN, et al. 2007. Developmental changes in histone macroH2A1-mediated gene regulation. Mol. Cell. Biol. 27:2758-2764.
Changolkar LN, et al. 2010. Genome-wide distribution of macroH2A1 histone variants in mouse liver chromatin. Mol. Cell. Biol. 30:5473-5483.
Dai B, Rasmussen TP. 2007. Global epiproteomic signatures distinguish embryonic stem cells from differentiated cells. Stem Cells 25:2567-2574.
Durinck S, Spellman PT, Birney E, Huber W. 2009. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat. Protoc. 4:1184-1191.
Evans MJ, Kaufman MH. 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154-156.
Feldman N, et al. 2006. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat. Cell Biol. 8:188-194.
Frank SR, Schroeder M, Fernandez P, Taubert S, Amati B. 2001. Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. Genes Dev. 15:2069-2082.
Gamble MJ, Frizzell KM, Yang C, Krishnakumar R, Kraus WL. 2010. The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing. Genes Dev. 24:21-32.
Gentleman RC, et al. 2004. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5:R80.
Heath JK, Smith AG. 1988. Regulatory factors of embryonic stem cells. J. Cell Sci. Suppl. 10:257-266.
Hemberger M, Dean W, Reik W. 2009. Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington's canal. Nat. Rev. Mol. Cell Biol. 10:526-537.
Hernandez-Munoz I, et al. 2005. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc. Natl. Acad. Sci. U. S. A. 102:7635-7640.
Honma M, Benitah SA, Watt FM. 2006. Role of LIM kinases in normal and psoriatic human epidermis. Mol. Biol. Cell 17:1888-1896.
Hooper M, Hardy K, Handyside A, Hunter S, Monk M. 1987. HPRTdeficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 326:292-295.
Huang DW, Sherman BT, Lempicki RA. 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4:44-57.
Kapoor A, et al. 2010. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature 468:1105-1109.
Langmead B, Trapnell C, Pop M, Salzberg SL. 2009. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10:R25.
Lichti U, Anders J, Yuspa SH. 2008. Isolation and short-term culture of primary keratinocytes, hair follicle populations and dermal cells from newborn mice and keratinocytes from adult mice for in vitro analysis and for grafting to immunodeficient mice. Nat. Protoc. 3:799-810.
Mietton F, et al. 2009. Weak but uniform enrichment of the histone variant macroH2A1 along the inactive X chromosome. Mol. Cell. Biol. 29:150-156.
Morey L, et al. 2012. Non-overlapping function of the Polycomb group Cbx family of proteins in embryonic stem cells. Cell Stem Cell 10:47-62.
Muller U. 1999. Ten years of gene targeting: targeted mouse mutants, from vector design to phenotype analysis. Mech. Dev. 82:3-21.
Niwa H. 2007. How is pluripotency determined and maintained? Development 134:635-646.
Novikov L, et al. 2011. QKI-mediated alternative splicing of the histone variant macroH2A1 regulates cancer cell proliferation. Mol. Cell. Biol. 31:4244-4255.
Ouararhni K, et al. 2006. The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. Genes Dev. 20:3324-3336.
Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. 2004. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23:4061-4071.
Pasque V, Gillich A, Garrett N, Gurdon JB. 2011. Histone variant macroH2A confers resistance to nuclear reprogramming. EMBO J. 30: 2373-2387.
Pehrson JR, Costanzi C, Dharia C. 1997. Developmental and tissue expression patterns of histone macroH2A1 subtypes. J. Cell Biochem. 65: 107-113.
Sarma K, Reinberg D. 2005. Histone variants meet their match. Nat. Rev. Mol. Cell Biol. 6:139-149.
Sporn JC, et al. 2009. Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene 28:3423-3428.
Tanasijevic B, Rasmussen TP. 2011. X chromosome inactivation and differentiation occur readily in ES cells doubly-deficient for macroH2A1 and macroH2A2. PLoS One 6:e21512.
Uribesalgo I, et al. 2011. E-box-independent regulation of transcription and differentiation by MYC. Nat. Cell Biol. 13:1443-1449.
Xu H, et al. 2010. A signal-noise model for significance analysis of ChIPseq with negative control. Bioinformatics 26:1199-1204.
Zhang Y, et al. 2008. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9:R137.
Zhu LJ, et al. 2010. ChIPpeakAnno: a Bioconductor package to annotate ChIP-seq and ChIP-chip data. BMC Bioinformatics 11:237.
