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

Dev Cell. 2024 Feb 26;59(4):465-481.e6. doi: 10.1016/j.devcel.2023.12.018. Epub 2024 Jan 17.

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.

Keywords: DNA methylation; DNMT3; R-loop; TET1; ZFP281; formative; naive; pluripotency; primed.

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Chromatin / metabolism
  • DNA / metabolism
  • DNA Methylation / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epigenesis, Genetic*
  • Germ Layers / metabolism
  • Mice
  • Pluripotent Stem Cells*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Transcription Factors / metabolism

Substances

  • Chromatin
  • DNA
  • Zfp281 protein, mouse
  • Transcription Factors
  • TET1 protein, mouse
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins