TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions

Cell Rep. 2021 Feb 23;34(8):108776. doi: 10.1016/j.celrep.2021.108776.

Abstract

Estrogen receptor-α (ER) drives tumor development in ER-positive (ER+) breast cancer. The transcription factor GATA3 has been closely linked to ER function, but its precise role in this setting remains unclear. Quantitative proteomics was used to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, few proteins were lost from the ER complex in the absence of GATA3, with the only major change being depletion of the dioxygenase TET2. TET2 binding constituted a near-total subset of ER binding in multiple breast cancer models, with loss of TET2 associated with reduced activation of proliferative pathways. TET2 knockdown did not appear to change global methylated cytosine (5mC) levels; however, oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) was significantly reduced, and these events occurred at ER enhancers. These findings implicate TET2 in the maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes.

Keywords: 5hmC; GATA3; TET2; enhancers; estrogen receptor; gene regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives*
  • 5-Methylcytosine / metabolism
  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Chromatin Assembly and Disassembly*
  • DNA Methylation*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Databases, Genetic
  • Dioxygenases / genetics
  • Dioxygenases / metabolism*
  • Enhancer Elements, Genetic*
  • Estrogen Receptor Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Fulvestrant / pharmacology
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • ESR1 protein, human
  • Estrogen Receptor Antagonists
  • Estrogen Receptor alpha
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • 5-hydroxymethylcytosine
  • Fulvestrant
  • 5-Methylcytosine
  • Dioxygenases
  • TET2 protein, human