Histone variants enriched in oocytes enhance reprogramming to induced pluripotent stem cells

Area of Science:

• Cell Biology
• Developmental Biology
• Epigenetics

Background:

• Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) using defined factors like Oct3/4, Sox2, Klf4, and c-Myc (OSKM).
• Somatic cell nuclear transfer (SCNT) is another reprogramming method, implying oocyte-derived factors can influence pluripotency induction.
• Histone variants TH2A and TH2B are highly expressed in oocytes and are involved in paternal genome activation post-fertilization.

Purpose of the Study:

• To investigate whether oocyte-specific histone variants TH2A and TH2B can enhance OSKM-mediated reprogramming.
• To determine if TH2A and TH2B can induce pluripotency with a reduced set of reprogramming factors.
• To explore the mechanism by which TH2A and TH2B might facilitate reprogramming.

Main Methods:

• Overexpression of histone variants TH2A and TH2B in somatic cells.
• Assessment of induced pluripotent stem cell (iPSC) generation efficiency with OSKM and modified factor combinations.
• Chromatin analysis, including DNase I sensitivity assays.
• Investigation of Xist deficiency effects on reprogramming with TH2A/TH2B.

Main Results:

• TH2A and TH2B significantly enhance OSKM-dependent iPSC generation.
• TH2A and TH2B alone, with Klf4 and Oct3/4, can induce reprogramming.
• TH2A and TH2B are enriched on the X chromosome during reprogramming and increase chromatin accessibility.
• Xist deficiency enhances TH2A/TH2B-mediated reprogramming with OSKM, but not OSKM alone.

Conclusions:

• Oocyte-specific histone variants TH2A and TH2B are potent enhancers of induced pluripotency.
• TH2A/TH2B may promote reprogramming by recapitulating aspects of zygotic activation and SCNT.
• These findings offer new strategies for improving iPSC generation efficiency.