BMP4 resets mouse epiblast stem cells to naive pluripotency through ZBTB7A/B-mediated chromatin remodelling

Nat Cell Biol. 2020 Jun;22(6):651-662. doi: 10.1038/s41556-020-0516-x. Epub 2020 May 11.

Abstract

BMP4 regulates a plethora of developmental processes, including the dorsal-ventral axis and neural patterning. Here, we report that BMP4 reconfigures the nuclear architecture during the primed-to-naive transition (PNT). We first established a BMP4-driven PNT and show that BMP4 orchestrates the chromatin accessibility dynamics during PNT. Among the loci opened early by BMP4, we identified Zbtb7a and Zbtb7b (Zbtb7a/b) as targets that drive PNT. ZBTB7A/B in turn facilitate the opening of naive pluripotent chromatin loci and the activation of nearby genes. Mechanistically, ZBTB7A not only binds to chromatin loci near to the genes that are activated, but also strategically occupies those that are silenced, consistent with a role of BMP4 in both activating and suppressing gene expression during PNT at the chromatin level. Our results reveal a previously unknown function of BMP4 in regulating nuclear architecture and link its targets ZBTB7A/B to chromatin remodelling and pluripotent fate control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blastocyst / cytology
  • Blastocyst / metabolism
  • Bone Morphogenetic Protein 4 / genetics
  • Bone Morphogenetic Protein 4 / metabolism*
  • Cell Differentiation
  • Cells, Cultured
  • Chromatin / genetics
  • Chromatin / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Germ Layers / cytology*
  • Germ Layers / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / metabolism
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Chromatin
  • DNA-Binding Proteins
  • Transcription Factors
  • Zbtb7a protein, mouse
  • Zbtb7b protein, mouse