TRPS1 regulates oestrogen receptor binding and histone acetylation at enhancers

Oncogene. 2018 Sep;37(39):5281-5291. doi: 10.1038/s41388-018-0312-2. Epub 2018 Jun 12.

Abstract

The chromatin state is finely tuned to regulate function and specificity for transcription factors such as oestrogen receptor alpha (ER), which contributes to cell growth in breast cancer. ER transcriptional potential is mediated, in large part, by the specific associated proteins and co-factors that interact with it. Despite the identification and characterisation of several ER coregulators, a complete and systematic view of ER-regulating chromatin modifiers is lacking. By exploiting a focused siRNA screen that investigated the requirement for a library of 330 chromatin regulators in ER-mediated cell growth, we find that the NuRD and coREST histone deacetylation complexes are critical for breast cancer cell proliferation. Further, by proteomic and genomics approaches, we discover the transcription factor TRPS1 to be a key interactor of the NuRD and coREST complexes. Interestingly, TRPS1 gene amplification occurs in 28% of human breast tumours and is associated with poor prognosis. We propose that TRPS1 is required to repress spurious binding of ER, where it contributes to the removal of histone acetylation. Our data suggest that TRPS1 is an important ER-associated transcriptional repressor that regulates cell proliferation, chromatin acetylation and ER binding at the chromatin of cis-regulatory elements.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Co-Repressor Proteins / genetics
  • Co-Repressor Proteins / metabolism
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Histones / metabolism
  • Humans
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Receptors, Estrogen / biosynthesis*
  • Receptors, Estrogen / genetics
  • Repressor Proteins
  • Transcription Factors / metabolism*
  • Transcriptional Activation / physiology

Substances

  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Histones
  • Nerve Tissue Proteins
  • RCOR1 protein, human
  • Receptors, Estrogen
  • Repressor Proteins
  • TRPS1 protein, human
  • Transcription Factors
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex