Tsix RNA and the germline factor, PRDM14, link X reactivation and stem cell reprogramming

Area of Science:

• Epigenetics
• Developmental Biology
• Stem Cell Biology

Background:

• Cellular differentiation involves epigenetic modifications, including X chromosome inactivation (XCI).
• Reprogramming to induced pluripotent stem cells (iPSCs) requires X chromosome reactivation (XCR), reversing XCI.
• The mechanisms governing XCR, particularly in reprogramming, remain poorly understood.

Purpose of the Study:

• To investigate the roles of the long noncoding RNA Tsix and the germline factor PRDM14 in X chromosome reactivation (XCR).
• To elucidate the functional and mechanistic links between Tsix, PRDM14, XCR, and pluripotency during cellular reprogramming.

Main Methods:

• Analysis of XCR in mouse blastocysts and induced pluripotent stem cells (iPSCs) with mutations or deficiencies in Tsix and Prdm14.
• Investigation of the molecular interactions between Tsix, PRDM14, Xist, Rnf12, and polycomb repressive complex 2 (PRC2).

Main Results:

• XCR in blastocysts is sensitive to mutations in both Tsix and Prdm14.
• PRDM14 deficiency disrupts XCR in iPSCs and impairs iPSC derivation and maintenance.
• PRDM14 represses Rnf12 via PRC2 recruitment, and Tsix facilitates PRDM14 binding to Xist.

Conclusions:

• Tsix RNA and PRDM14 are critical regulators of X chromosome reactivation during cellular reprogramming.
• These factors establish a direct link between X chromosome dynamics and the maintenance of pluripotency.
• The findings provide mechanistic insights into the interplay between epigenetic reprogramming and stem cell pluripotency.