Expression of Oct3/4, Sox2, Klf4, and c-Myc (OSKM) can reprogram somatic cells into induced pluripotent stem cells (iPSCs). Somatic cell nuclear transfer (SCNT) can also be used for reprogramming, suggesting that factors present in oocytes could potentially augment OSKM-mediated induction of pluripotency. Here, we report that two histone variants, TH2A and TH2B, which are highly expressed in oocytes and contribute to activation of the paternal genome after fertilization, enhance OSKM-dependent generation of iPSCs and can induce reprogramming with Klf4 and Oct3/4 alone. TH2A and TH2B are enriched on the X chromosome during the reprogramming process, and their expression in somatic cells increases the DNase I sensitivity of chromatin. In addition, Xist deficiency, which was reported to enhance SCNT reprogramming efficiency, stimulates iPSC generation using TH2A/TH2B in conjunction with OSKM, but not OSKM alone. Thus, TH2A/TH2B may enhance reprogramming by introducing processes that normally operate in zygotes and during SCNT.
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