Transcription factor MITF and remodeller BRG1 define chromatin organisation at regulatory elements in melanoma cells

Elife. 2015 Mar 24;4:e06857. doi: 10.7554/eLife.06857.

Abstract

Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. To understand how MITF regulates transcription, we used tandem affinity purification and mass spectrometry to define a comprehensive MITF interactome identifying novel cofactors involved in transcription, DNA replication and repair, and chromatin organisation. We show that MITF interacts with a PBAF chromatin remodelling complex comprising BRG1 and CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. Combinations of MITF, SOX10, TFAP2A, and YY1 bind between two BRG1-occupied nucleosomes thus defining both a signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of the regulatory elements they occupy. BRG1 also regulates the dynamics of MITF genomic occupancy. MITF-BRG1 interplay thus plays an essential role in transcription regulation in melanoma.

Keywords: CHD7; SOX10; TFAP2A; YY1; biochemistry; chromatin remodelling; chromosomes; enhancer; genes; human; mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly*
  • DNA Helicases / metabolism*
  • DNA Repair / genetics
  • DNA Replication / genetics
  • Gene Expression Regulation, Neoplastic
  • Genome
  • Humans
  • Melanocytes / metabolism
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mice
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Models, Biological
  • Multiprotein Complexes / metabolism
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Transport
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • Chromatin
  • Microphthalmia-Associated Transcription Factor
  • Multiprotein Complexes
  • Nuclear Proteins
  • Transcription Factors
  • SMARCA4 protein, human
  • Smarca4 protein, mouse
  • DNA Helicases

Associated data

  • GEO/GSE61967