H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs

Jiekai Chen; He Liu; Jing Liu; Jing Qi; Bei Wei; Jiaqi Yang; Hanquan Liang; You Chen; Jing Chen; Yaran Wu; Lin Guo; Jieying Zhu; Xiangjie Zhao; Tianran Peng; Yixin Zhang; Shen Chen; Xuejia Li; Dongwei Li; Tao Wang; Duanqing Pei

doi:10.1038/ng.2491

H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs

Jiekai Chen^#; He Liu^#; Jing Liu; Jing Qi; Bei Wei; Jiaqi Yang; Hanquan Liang; You Chen; Jing Chen; Yaran Wu; Lin Guo; Jieying Zhu; Xiangjie Zhao; Tianran Peng; Yixin Zhang; Shen Chen; Xuejia Li; Dongwei Li; Tao Wang; Duanqing Pei^*

Nature Genetics, 2013, 45(1): 34-42.

DOI: 10.1038/ng.2491

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Summary

The induction of pluripotent stem cells (iPSCs) by defined factors is poorly understood stepwise. Here, we show that histone H3 lysine 9 (H3K9) methylation is the primary epigenetic determinant for the intermediate pre-iPSC state, and its removal leads to fully reprogrammed iPSCs. We generated a panel of stable pre-iPSCs that exhibit pluripotent properties but do not activate the core pluripotency network, although they remain sensitive to vitamin C for conversion into iPSCs. Bone morphogenetic proteins (BMPs) were subsequently identified in serum as critical signaling molecules in arresting reprogramming at the pre-iPSC state. Mechanistically, we identified H3K9 methyltransferases as downstream targets of BMPs and showed that they function with their corresponding demethylases as the on/off switch for the pre-iPSC fate by regulating H3K9 methylation status at the core pluripotency loci. Our results not only establish pre-iPSCs as an epigenetically stable signpost along the reprogramming road map, but they also provide mechanistic insights into the epigenetic reprogramming of cell fate.

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