Inhibition of Aberrant DNA Re-methylation Improves Post-implantation Development of Somatic Cell Nuclear Transfer Embryos

Cell Stem Cell
Rui GaoShaorong Gao

Abstract

Somatic cell nuclear transfer (SCNT) enables cloning of differentiated cells by reprogramming their nuclei to a totipotent state. However, successful full-term development of SCNT embryos is a low-efficiency process and arrested embryos frequently exhibit epigenetic abnormalities. Here, we generated genome-wide DNA methylation maps from mouse pre-implantation SCNT embryos. We identified widespread regions that were aberrantly re-methylated, leading to mis-expression of genes and retrotransposons important for zygotic genome activation. Inhibition of DNA methyltransferases (Dnmts) specifically rescued these re-methylation defects and improved the developmental capacity of cloned embryos. Moreover, combining inhibition of Dnmts with overexpression of histone demethylases led to stronger reductions in inappropriate DNA methylation and synergistic enhancement of full-term SCNT embryo development. These findings show that excessive DNA re-methylation is a potent barrier that limits full-term development of SCNT embryos and that removing multiple epigenetic barriers is a promising approach to achieve higher cloning efficiency.

Citations

Dec 15, 2019·Reproduction in Domestic Animals = Zuchthygiene·Yumei ZhangJian Hou
Sep 20, 2019·Epigenetics : Official Journal of the DNA Methylation Society·Panpan ZhaoKun Zhang
Oct 28, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lei YangGuangpeng Li
Feb 20, 2020·Stem Cell Research & Therapy·Pengxiang QuEnqi Liu
Feb 13, 2019·The Journal of Reproduction and Development·Kei Miyamoto
Mar 20, 2019·Cellular and Molecular Life Sciences : CMLS·Wenteng HeShaorong Gao
Nov 16, 2020·The FEBS Journal·Dilşad H ArabacıTamer T Önder
Jan 1, 2021·International Journal of Molecular Sciences·Kilian SimmetValeri Zakhartchenko
Apr 17, 2021·Cellular Reprogramming·Tahmineh TooraniGabriela F Mastromonaco
Jun 12, 2021·Frontiers in Cell and Developmental Biology·Pengbo CaoBuhe Nashun
Feb 22, 2021·Genomics, Proteomics & Bioinformatics·Xinxin WangJiang Liu
Aug 8, 2021·International Journal of Molecular Sciences·Chunshen LongYongchun Zuo

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