Genome-wide analysis reveals a role for TDG in estrogen receptor-mediated enhancer RNA transcription and 3-dimensional reorganization

Epigenetics Chromatin. 2018 Jan 29;11(1):5. doi: 10.1186/s13072-018-0176-2.

Abstract

Background: The estrogen receptor (ER) is a ligand-dependant transcription factor expressed in many breast cancers and is the target of many endocrine-based cancer therapies. Genome-wide studies have shown that the ER binds to gene-specific enhancer regions in response to β-estradiol (E2) which undergo transcription producing noncoding enhancer RNA (eRNA). While eRNAs are important for transcriptional activation of neighboring genes, the mechanism remains poorly understood.

Results: Using ChIP-Seq we generate a global profile of thymine DNA glycosylase (TDG), an ER coactivator that plays an essential role in DNA demethylation, in response to E2 in the MCF7 breast cancer cell line. Remarkably, we found that in response to E2 TDG localized to enhancers which also recruit ERα, RNA Pol II and other coregulators and which are marked by histone modifications indicative of active enhancers. Importantly, depletion of TDG inhibits E2-mediated transcription of eRNAs and transcription of ER-target genes. Functionally, we find that TDG both sensitizes MCF7 cells to tamoxifen-mediated cytostasis and increases migration and invasion of MCF7 cells.

Conclusions: Taken together we find that TDG plays a central role in mediating transcription at a subset of enhancers and governs how MCF7 cells respond to both estrogenic and anti-estrogenic compounds and may be an effective therapeutic target.

Keywords: Cancer; Estrogen receptor; Estrogen signaling; Thymine DNA glycosylase; eRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chromatin Immunoprecipitation
  • DNA Methylation
  • Drug Synergism
  • Enhancer Elements, Genetic*
  • Estradiol / pharmacology*
  • Female
  • Humans
  • MCF-7 Cells
  • RNA Polymerase II / genetics
  • Receptors, Estrogen / metabolism*
  • Sequence Analysis, RNA / methods*
  • Tamoxifen / pharmacology*
  • Thymine DNA Glycosylase / genetics
  • Whole Genome Sequencing / methods

Substances

  • Receptors, Estrogen
  • Tamoxifen
  • Estradiol
  • RNA Polymerase II
  • Thymine DNA Glycosylase

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