Chromatin-Remodelling Complex NURF Is Essential for Differentiation of Adult Melanocyte Stem Cells

PLoS Genet. 2015 Oct 6;11(10):e1005555. doi: 10.1371/journal.pgen.1005555. eCollection 2015 Oct.

Abstract

MIcrophthalmia-associated Transcription Factor (MITF) regulates melanocyte and melanoma physiology. We show that MITF associates the NURF chromatin-remodelling factor in melanoma cells. ShRNA-mediated silencing of the NURF subunit BPTF revealed its essential role in several melanoma cell lines and in untransformed melanocytes in vitro. Comparative RNA-seq shows that MITF and BPTF co-regulate overlapping gene expression programs in cell lines in vitro. Somatic and specific inactivation of Bptf in developing murine melanoblasts in vivo shows that Bptf regulates their proliferation, migration and morphology. Once born, Bptf-mutant mice display premature greying where the second post-natal coat is white. This second coat is normally pigmented by differentiated melanocytes derived from the adult melanocyte stem cell (MSC) population that is stimulated to proliferate and differentiate at anagen. An MSC population is established and maintained throughout the life of the Bptf-mutant mice, but these MSCs are abnormal and at anagen, give rise to reduced numbers of transient amplifying cells (TACs) that do not express melanocyte markers and fail to differentiate into mature melanin producing melanocytes. MSCs display a transcriptionally repressed chromatin state and Bptf is essential for reactivation of the melanocyte gene expression program at anagen, the subsequent normal proliferation of TACs and their differentiation into mature melanocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Nuclear / genetics*
  • Cell Cycle / genetics
  • Cell Differentiation / genetics
  • Cell Division / genetics
  • Chromatin Assembly and Disassembly / genetics*
  • Gene Expression Regulation, Developmental
  • Hair Follicle
  • Melanocytes / metabolism
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mesenchymal Stem Cells*
  • Mice
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Nerve Tissue Proteins / genetics*
  • Transcription Factors / genetics*

Substances

  • Antigens, Nuclear
  • Microphthalmia-Associated Transcription Factor
  • Mitf protein, mouse
  • Nerve Tissue Proteins
  • Transcription Factors
  • fetal Alzheimer antigen

Grant support

This work was supported by grants from the CNRS, the INSERM, the Fondation ARC, the Ligue Nationale et Départementale contre le Cancer (Régions Alsace et Oise), the Institut National du Cancer (INCa) PAIR melanoma (MELA13-002), Cancéropole IdF, the ANR-10-LABX-0030-INRT French state fund through the ANR under the programme Investissements d’Avenir labelled ANR-10-IDEX-0002-02 and the Labex CelTisPhyBio (ANR-11-LBX-0038) under ANR-10-IDEX-0001-02. ID and LL are ‘équipe labellisées’ of the Ligue Nationale contre le Cancer. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.