The Accessible Chromatin Landscape During Conversion of Human Embryonic Stem Cells to Trophoblast by Bone Morphogenetic Protein 4

Biol Reprod. 2017 Jun 1;96(6):1267-1278. doi: 10.1093/biolre/iox028.

Abstract

Human embryonic stem cells (hESCs) exposed to the growth factor bone morphogenetic protein 4 (BMP4) in the absence of FGF2 have been used as a model to study the development of placental development. However, little is known about the cis-regulatory mechanisms underlying this important process. In this study, we used the public available chromatin accessibility data of hESC H1 cells and BMP4-induced trophoblast (TB) cell lines to identify DNase I hypersensitive sites (DHSs) in the two cell lines, as well as the transcription factor (TF) binding sites within the DHSs. By comparing read profiles in H1 and TB, we identified 17 472 TB-specific DHSs. The TB-specific DHSs are enriched in terms of "blood vessel" and "trophectoderm," consisting of TF motifs family: Leucine Zipper, Helix-Loop-Helix, GATA, and ETS. To validate differential expression of the TFs binding to these motifs, we analyzed public available RNA-seq and microarray data in the same context. Finally, by integrating the protein-protein interaction data, we constructed a TF network for placenta development and identified top 20 key TFs through centrality analysis in the network. Our results indicate BMP4-induced TB system provided an invaluable model for the study of TB development and highlighted novel candidate genes in placenta development in human.

Keywords: DNase I hypersensitive sites; TF Network; cis-regulation; placental development.

MeSH terms

  • Animals
  • Base Sequence
  • Bone Morphogenetic Protein 4 / pharmacology*
  • Cell Differentiation / physiology
  • Cell Line
  • Chromatin*
  • Embryonic Stem Cells / physiology*
  • Female
  • Gene Expression Regulation, Developmental
  • Human Embryonic Stem Cells
  • Humans
  • Placentation
  • Pregnancy
  • RNA / genetics
  • Trophoblasts / physiology*

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • Chromatin
  • RNA