Super-enhancer-guided mapping of regulatory networks controlling mouse trophoblast stem cells

Nat Commun. 2019 Oct 18;10(1):4749. doi: 10.1038/s41467-019-12720-6.


Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy. However, only a few TE-specific transcription factors (TFs) have been systematically characterized, hindering our understanding of the process. To elucidate regulatory mechanisms underlying TE development, here we map super-enhancers (SEs) in trophoblast stem cells (TSCs) as a model. We find both prominent TE-specific master TFs (Cdx2, Gata3, and Tead4), and >150 TFs that had not been previously implicated in TE lineage, that are SE-associated. Mapping targets of 27 SE-predicted TFs reveals a highly intertwined transcriptional regulatory circuitry. Intriguingly, SE-predicted TFs show 4 distinct expression patterns with dynamic alterations of their targets during TSC differentiation. Furthermore, depletion of a subset of TFs results in dysregulation of the markers for specialized cell types in placenta, suggesting a role during TE differentiation. Collectively, we characterize an expanded TE-specific regulatory network, providing a framework for understanding TE lineage development and placentation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Lineage / genetics
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / embryology
  • Embryo, Mammalian / metabolism
  • Embryonic Stem Cells / metabolism*
  • Enhancer Elements, Genetic / genetics*
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Developmental*
  • Gene Regulatory Networks*
  • Mice
  • Placentation / genetics
  • Pregnancy
  • Transcription Factors / genetics
  • Trophoblasts / cytology
  • Trophoblasts / metabolism*


  • Transcription Factors