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, Emily Bernstein

Research output: Contribution to journalArticle

105 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1565
JournalNature Communications
Volume4
DOIs
StatePublished - Apr 11 2013
Externally publishedYes

Fingerprint

Protein Isoforms
Genes
genes
Fibroblasts
Epigenomics
fibroblasts
cells
knockout mice
Knockout Mice
Histones
chromatin
Chromatin
stems
manipulators
templates
macroH2A histone
In Vitro Techniques
Cellular Reprogramming

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Gaspar Maia, A., Qadeer, Z. A., Hasson, D., Ratnakumar, K., Adrian Leu, N., Leroy, G., ... Bernstein, E. (2013). MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. Nature Communications, 4, [1565]. https://doi.org/10.1038/ncomms2582

MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. / Gaspar Maia, Alexandre; Qadeer, Zulekha A.; Hasson, Dan; Ratnakumar, Kajan; Adrian Leu, N.; Leroy, Gary; Liu, Shichong; Costanzi, Carl; Valle-Garcia, David; Schaniel, Christoph; Lemischka, Ihor; Garcia, Benjamin; Pehrson, John R.; Bernstein, Emily.

In: Nature Communications, Vol. 4, 1565, 11.04.2013.

Research output: Contribution to journalArticle

Gaspar Maia, A, Qadeer, ZA, Hasson, D, Ratnakumar, K, Adrian Leu, N, Leroy, G, Liu, S, Costanzi, C, Valle-Garcia, D, Schaniel, C, Lemischka, I, Garcia, B, Pehrson, JR & Bernstein, E 2013, 'MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency', Nature Communications, vol. 4, 1565. https://doi.org/10.1038/ncomms2582
Gaspar Maia, Alexandre ; Qadeer, Zulekha A. ; Hasson, Dan ; Ratnakumar, Kajan ; Adrian Leu, N. ; Leroy, Gary ; Liu, Shichong ; Costanzi, Carl ; Valle-Garcia, David ; Schaniel, Christoph ; Lemischka, Ihor ; Garcia, Benjamin ; Pehrson, John R. ; Bernstein, Emily. / MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. In: Nature Communications. 2013 ; Vol. 4.
@article{6e7045e7feaf4b30a019e0cdc5fb2bf1,
title = "MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency",
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.",
author = "{Gaspar Maia}, Alexandre and Qadeer, {Zulekha A.} and Dan Hasson and Kajan Ratnakumar and {Adrian Leu}, N. and Gary Leroy and Shichong Liu and Carl Costanzi and David Valle-Garcia and Christoph Schaniel and Ihor Lemischka and Benjamin Garcia and Pehrson, {John R.} and Emily Bernstein",
year = "2013",
month = "4",
day = "11",
doi = "10.1038/ncomms2582",
language = "English (US)",
volume = "4",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency

AU - Gaspar Maia, Alexandre

AU - Qadeer, Zulekha A.

AU - Hasson, Dan

AU - Ratnakumar, Kajan

AU - Adrian Leu, N.

AU - Leroy, Gary

AU - Liu, Shichong

AU - Costanzi, Carl

AU - Valle-Garcia, David

AU - Schaniel, Christoph

AU - Lemischka, Ihor

AU - Garcia, Benjamin

AU - Pehrson, John R.

AU - Bernstein, Emily

PY - 2013/4/11

Y1 - 2013/4/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84875887547&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875887547&partnerID=8YFLogxK

U2 - 10.1038/ncomms2582

DO - 10.1038/ncomms2582

M3 - Article

VL - 4

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 1565

ER -