Methylome inheritance and enhancer dememorization reset an epigenetic gate safeguarding embryonic programs
Xiaotong Wu, Xiaotong Wu, Hongmei Zhang, Bingjie Zhang, Yu Zhang, Qiuyan Wang, Weimin Shen, Xi Wu, Xi Wu, Lijia Li, Weikun Xia, Ryohei Nakamura, Bofeng Liu, Feng Liu, Hiroyuki Takeda, Anming Meng, Wei Xie
Abstract
using oocyte microinjection, we eliminated DNA methylation in early embryos, which died around gastrulation with severe differentiation defects. Notably, methylation deficiency leads to derepression of adult tissue–specific genes and CG-rich enhancers, which acquire ectopic transcription factor binding and, unexpectedly, histone H3 lysine 4 trimethylation (H3K4me3). By contrast, embryonic enhancers are generally CG-poor and evade DNA methylation repression. Hence, global DNA hypermethylation inheritance coupled with enhancer dememorization installs an epigenetic gate that safeguards embryonic programs and ensures temporally ordered gene expression. We propose that “enhancer dememorization” underlies and unifies distinct epigenetic reprogramming modes in early development between mammals and nonmammals.