Coordination of germ layer lineage choice by TET1 during primed pluripotency

Genes Dev. 2020 Apr 1;34(7-8):598-618. doi: 10.1101/gad.329474.119. Epub 2020 Feb 27.


Gastrulation in the early postimplantation stage mammalian embryo begins when epiblast cells ingress to form the primitive streak or develop as the embryonic ectoderm. The DNA dioxygenase Tet1 is highly expressed in the epiblast and yet continues to regulate lineage specification during gastrulation when its expression is diminished. Here, we show how Tet1 plays a pivotal role upstream of germ layer lineage bifurcation. During the transition from naive pluripotency to lineage priming, a global reconfiguration redistributes Tet1 from Oct4-cobound promoters to distal regulatory elements at lineage differentiation genes, which are distinct from high-affinity sites engaged by Oct4. An altered chromatin landscape in Tet1-deficient primed epiblast-like cells is associated with enhanced Oct4 expression and binding to Nodal and Wnt target genes, resulting in collaborative signals that enhance mesendodermal and inhibit neuroectodermal gene expression during lineage segregation. A permissive role for Tet1 in neural fate induction involves Zic2-dependent engagement at neural target genes at lineage priming, is dependent on the signaling environment during gastrulation, and impacts neural tube closure after gastrulation. Our findings provide mechanistic information for epigenetic integration of pluripotency and signal-induced differentiation cues.

Keywords: cell fate; chromatin accessibility; developmental signaling; epigenetics; germ layer segregation; pluripotency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cell Lineage / genetics*
  • Cells, Cultured
  • Chromatin / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Embryo, Mammalian
  • Gene Deletion
  • Gene Expression Regulation, Developmental
  • Germ Layers / metabolism
  • Mice
  • Octamer Transcription Factor-3 / metabolism
  • Pluripotent Stem Cells / cytology*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction / genetics
  • Transcription Factors / metabolism


  • Chromatin
  • DNA-Binding Proteins
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • Transcription Factors
  • Zic2 protein, mouse