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

Dana Koludrovic,Lionel Larue,Madeleine Le Coz,Patrick Laurette,Irwin Davidson,Céline Keime,Sebastien Coassolo,Thomas Strub,Gabrielle Mengus,Wendy A Bickmore

doi:10.1371/journal.pgen.1005555

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.

Highlights

MIcrophthalmia-associated Transcription Factor (MITF) is a basic helix-loop-helix leucine zipper factor playing an essential role in the differentiation, survival, and proliferation of normal melanocytes, and in controlling the melanoma cell physiology [1,2,3,4]
The melanocytes pigmenting the coat of adult mice derive from the melanocyte stem cell population residing in the permanent bulge area of the hair follicle
Melanocyte stem cells are stimulated to generate proliferative transient amplifying cells that migrate to the bulb of the follicle where they differentiate into mature melanin producing melanocytes, a processes involving MIcrophthalmia-associated Transcription

Summary

Introduction

MIcrophthalmia-associated Transcription Factor (MITF) is a basic helix-loop-helix leucine zipper (bHLH-Zip) factor playing an essential role in the differentiation, survival, and proliferation of normal melanocytes, and in controlling the melanoma cell physiology [1,2,3,4]. MITF silencing in proliferative melanoma cells leads to cell cycle arrest and entry into senescence [11,12]. These and other observations gave rise to the proposed ‘rheostat’ model postulating that the level of functional MITF expression determines many biological properties of melanocytes and melanoma cells [13,14]. MSCs and slow cycling melanoma cells express low or no MITF, while TACs and proliferative melanoma cells express higher levels. High MITF activity induces terminal melanocyte differentiation and can induce cell cycle arrest of melanoma cells [15]. This property has been exploited to derive drugs that induce terminal differentiation of melanoma cells as a therapy for melanoma [16]

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