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Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency

Pasque, Vincent and Radzisheuskaya, Aliaksandra and Gillich, Astrid and Halley-Stott, Richard P. and Panamarova, Maryna and Zernicka-Goetz, Magdalena and Surani, M. Azim and Silva, José C. R. (2012) Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. Journal of Cell Science, 125 (24). pp. 6094-6104. ISSN 0021-9533. PMCID PMC3585521. doi:10.1242/jcs.113019.

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How cell fate becomes restricted during somatic cell differentiation is a long-lasting question in biology. Epigenetic mechanisms not present in pluripotent cells and acquired during embryonic development are expected to stabilize the differentiated state of somatic cells and thereby restrict their ability to convert to another fate. The histone variant macroH2A acts as a component of an epigenetic multilayer that heritably maintains the silent X chromosome and has been shown to restrict tumor development. Here we show that macroH2A marks the differentiated cell state during mouse embryogenesis. MacroH2A.1 was found to be present at low levels upon the establishment of pluripotency in the inner cell mass and epiblast, but it was highly enriched in the trophectoderm and differentiated somatic cells later in mouse development. Chromatin immunoprecipitation revealed that macroH2A.1 is incorporated in the chromatin of regulatory regions of pluripotency genes in somatic cells such as mouse embryonic fibroblasts and adult neural stem cells, but not in embryonic stem cells. Removal of macroH2A.1, macroH2A.2 or both increased the efficiency of induced pluripotency up to 25-fold. The obtained induced pluripotent stem cells reactivated pluripotency genes, silenced retroviral transgenes and contributed to chimeras. In addition, overexpression of macroH2A isoforms prevented efficient reprogramming of epiblast stem cells to naïve pluripotency. In summary, our study identifies for the first time a link between an epigenetic mark and cell fate restriction during somatic cell differentiation, which helps to maintain cell identity and antagonizes induction of a pluripotent stem cell state.

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URLURL TypeDescription CentralArticle Information
Zernicka-Goetz, Magdalena0000-0002-7004-2471
Additional Information:© 2012 The Company of Biologists. Accepted 24 September 2012. The authors are indebt to Dr John Gurdon for his support as well as comments on the manuscript and to Dr Jennifer Nichols for advice on antibody staining on early embryos. We are very grateful to Dr Theodore Rasmussen for his kind gift of macroH2A.1 antibody. We thank William Mansfield and Charles-Etienne Dumeau for performing blastocyst injections and teratoma assays and Margaret McLeish for histological processing of the teratomas. Astrid Gillich, Richard P. Halley-Stott and Maryna Panamarova made equal contribution as second authors to this paper. The authors declare that they have no conflict of interest. This work was supported by The Wellcome Trust [grant numbers RG54943, 081277 and RG44593]. J.S. is a Wellcome Trust Career Development Fellow [grant number WT086692]. M.P. and M.Z.-G. are supported by a Wellcome Trust Senior Fellowship to M.Z.-G. V.P. was also supported by a Wallonia-Brussels International Excellence Grant; A.R. and M.P. by the Darwin Trust of Edinburgh; and R.P.H.-S. by the Medical Research Council. Deposited in PMC for immediate release.
Funding AgencyGrant Number
Wellcome TrustRG54943
Wellcome Trust081277
Wellcome TrustRG44593
Wellcome TrustWT086692
Wallonia-Brussels International Excellence GrantUNSPECIFIED
Darwin Trust of EdinburghUNSPECIFIED
Medical Research Council (UK)UNSPECIFIED
Subject Keywords:Cell commitment, Epigenetic stability, Induced pluripotency, macroH2A, Nuclear reprogramming
Issue or Number:24
PubMed Central ID:PMC3585521
Record Number:CaltechAUTHORS:20190417-152709124
Persistent URL:
Official Citation:Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency Vincent Pasque, Aliaksandra Radzisheuskaya, Astrid Gillich, Richard P. Halley-Stott, Maryna Panamarova, Magdalena Zernicka-Goetz, M. Azim Surani, José C. R. Silva J Cell Sci 2012 125: 6094-6104; doi: 10.1242/jcs.113019
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94757
Deposited By: George Porter
Deposited On:18 Apr 2019 14:31
Last Modified:16 Nov 2021 17:07

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