TET1 and 5-Hydroxymethylation Preserve the Stem Cell State of Mouse Trophoblast

Stem Cell Reports. 2020 Dec 8;15(6):1301-1316. doi: 10.1016/j.stemcr.2020.04.009. Epub 2020 May 21.

Abstract

The ten-eleven translocation factor TET1 and its conferred epigenetic modification 5-hydroxymethylcytosine (5hmC) have important roles in maintaining the pluripotent state of embryonic stem cells (ESCs). We previously showed that TET1 is also essential to maintain the stem cell state of trophoblast stem cells (TSCs). Here, we establish an integrated panel of absolute 5hmC levels, genome-wide DNA methylation and hydroxymethylation patterns, transcriptomes, and TET1 chromatin occupancy in TSCs and differentiated trophoblast cells. We show that the combined presence of 5-methylcytosine (5mC) and 5hmC correlates with transcriptional activity of associated genes. Hypoxia can slow down the global loss of 5hmC that occurs upon differentiation of TSCs. Notably, unlike in ESCs and epiblast cells, most TET1-bound regions overlap with active chromatin marks and TFAP2C binding sites and demarcate putative trophoblast enhancer regions. These chromatin modification and occupancy patterns are highly informative to identify novel candidate regulators of the TSC state.

Keywords: DNA hydroxymethylation; DNA methylation; TET1; chromatin interactions; embryonic stem cells; enhancers; epigenetics; gene regulation; trophoblast stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia
  • DNA Methylation*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enhancer Elements, Genetic
  • Mice
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Transcription Factor AP-2 / genetics
  • Transcription Factor AP-2 / metabolism
  • Trophoblasts / cytology
  • Trophoblasts / metabolism*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • Tfap2c protein, mouse
  • Transcription Factor AP-2