ZFP281 controls transcriptional and epigenetic changes promoting mouse pluripotent state transitions via DNMT3 and TET1

Xin Huang, Sophie Balmer, Cong Lyu, Yunlong Xiang, Vikas Malik, Hailin Wang, Yu Zhang, Bishuang Cai, Wei Xie, Anna Katerina Hadjantonakis, Hongwei Zhou, Jianlong Wang

Research output: Contribution to journalArticlepeer-review

Abstract

The progression from naive through formative to primed in vitro pluripotent stem cell states recapitulates epiblast development in vivo during the peri-implantation period of mouse embryo development. Activation of the de novo DNA methyltransferases and reorganization of transcriptional and epigenetic landscapes are key events that occur during these pluripotent state transitions. However, the upstream regulators that coordinate these events are relatively underexplored. Here, using Zfp281 knockout mouse and degron knockin cell models, we identify the direct transcriptional activation of Dnmt3a/3b by ZFP281 in pluripotent stem cells. Chromatin co-occupancy of ZFP281 and DNA hydroxylase TET1, which is dependent on the formation of R-loops in ZFP281-targeted gene promoters, undergoes a “high-low-high” bimodal pattern regulating dynamic DNA methylation and gene expression during the naive-formative-primed transitions. ZFP281 also safeguards DNA methylation in maintaining primed pluripotency. Our study demonstrates a previously unappreciated role for ZFP281 in coordinating DNMT3A/3B and TET1 functions to promote pluripotent state transitions.

Original languageEnglish
Pages (from-to)465-481.e6
JournalDevelopmental Cell
Volume59
Issue number4
DOIs
StatePublished - 26 Feb 2024

Keywords

  • DNA methylation
  • DNMT3
  • R-loop
  • TET1
  • ZFP281
  • formative
  • naive
  • pluripotency
  • primed

Fingerprint

Dive into the research topics of 'ZFP281 controls transcriptional and epigenetic changes promoting mouse pluripotent state transitions via DNMT3 and TET1'. Together they form a unique fingerprint.

Cite this