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EMBO J May 6, 2011; 30 (12): 2373-87.

Histone variant macroH2A confers resistance to nuclear reprogramming.

Pasque V , Gillich A , Garrett N , Gurdon JB .

How various layers of epigenetic repression restrict somatic cell nuclear reprogramming is poorly understood. The transfer of mammalian somatic cell nuclei into Xenopus oocytes induces transcriptional reprogramming of previously repressed genes. Here, we address the mechanisms that restrict reprogramming following nuclear transfer by assessing the stability of the inactive X chromosome (Xi) in different stages of inactivation. We find that the Xi of mouse post-implantation-derived epiblast stem cells (EpiSCs) can be reversed by nuclear transfer, while the Xi of differentiated or extraembryonic cells is irreversible by nuclear transfer to oocytes. After nuclear transfer, Xist RNA is lost from chromatin of the Xi. Most epigenetic marks such as DNA methylation and Polycomb-deposited H3K27me3 do not explain the differences between reversible and irreversible Xi. Resistance to reprogramming is associated with incorporation of the histone variant macroH2A, which is retained on the Xi of differentiated cells, but absent from the Xi of EpiSCs. Our results uncover the decreased stability of the Xi in EpiSCs, and highlight the importance of combinatorial epigenetic repression involving macroH2A in restricting transcriptional reprogramming by oocytes.

PubMed ID: 21552206
PMC ID: PMC3116279
Article link: EMBO J
Grant support: [+]

Species referenced: Xenopus
Genes referenced: bmi1 hprt1 kcnma1 macroh2a1 pou5f3.1 prkg1 rlim sox2 uba1 xa-1

Article Images: [+] show captions
References [+] :
Abbott, Beyond the Xi: macroH2A chromatin distribution and post-translational modification in an avian system. 2005, Pubmed