MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency

Alexandre Gaspar-Maia, Zulekha A. Qadeer, Dan Hasson, Kajan Ratnakumar, N. Adrian Leu, Gary Leroy, Shichong Liu, Carl Costanzi, David Valle-Garcia, Christoph Schaniel, Ihor Lemischka, Benjamin Garcia, John R. Pehrson and Emily Bernstein ()
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Alexandre Gaspar-Maia: Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
Zulekha A. Qadeer: Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
Dan Hasson: Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
Kajan Ratnakumar: Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
N. Adrian Leu: School of Veterinary Medicine, University of Pennsylvania
Gary Leroy: Princeton University, 415 Schultz Laboratory
Shichong Liu: Princeton University, 415 Schultz Laboratory
Carl Costanzi: School of Veterinary Medicine, University of Pennsylvania
David Valle-Garcia: Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA
Christoph Schaniel: Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai 1425 Madison Avenue, New York, New York 10029, USA
Ihor Lemischka: Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai 1425 Madison Avenue, New York, New York 10029, USA
Benjamin Garcia: Princeton University, 415 Schultz Laboratory
John R. Pehrson: School of Veterinary Medicine, University of Pennsylvania
Emily Bernstein: Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, New York 10029, USA

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract The chromatin template imposes an epigenetic barrier during the process of somatic cell reprogramming. Using fibroblasts derived from macroH2A double knockout (dKO) mice, here we show that these histone variants act cooperatively as a barrier to induced pluripotency. Through manipulation of macroH2A isoforms, we further demonstrate that macroH2A2 is the predominant barrier to reprogramming. Genomic analyses reveal that macroH2A1 and macroH2A2, together with H3K27me3, co-occupy pluripotency genes in wild-type (wt) fibroblasts. In particular, we find macroH2A isoforms to be highly enriched at target genes of the K27me3 demethylase, Utx, which are reactivated early in iPS reprogramming. Finally, while macroH2A dKO-induced pluripotent cells are able to differentiate properly in vitro and in vivo, such differentiated cells retain the ability to return to a stem-like state. Therefore, we propose that macroH2A isoforms provide a redundant silencing layer or terminal differentiation ‘lock’ at critical pluripotency genes that presents as an epigenetic barrier when differentiated cells are challenged to reprogram.

Date: 2013
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DOI: 10.1038/ncomms2582

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