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

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.

BPTF transduces MITF-driven prosurvival signals in melanoma cells

“…Importantly, melanomas with high MITF expression were found to express significantly higher levels of BPTF than melanomas with low MITF expression. Recently, BPTF was shown to be essential for differentiation of murine melanocytic stem cells (19). In addition, MITF and BPTF were shown to coregulate overlapping gene-expression programs in melanoma cells and melanocytes, supporting our results.…”

MITF—the first 25 years

“…Consistent with MITF shuttling in and out of the nucleus (see below), several nuclear pore components were identified, including IPO5, together with RNA polymerase III cofactors and cohesin subunits (SMCA1, SMC3, STAG2, and PDS5). Although the biological consequences of many of the interactions identified remain to be determined, interaction with several components of the NURF chromatin remodeling complex (BPTF, SMARCA1 [SNF2L], SMARCA5 [SNF2H], and RBBP4 [RbAP48]) led Koludrovic et al (2015) to examine the role of NURF in melanoma/melanocyte biology. The results indicate that NURF is implicated in a gene expression program that overlaps with MITF, and is required for proliferation, migration, and morphology in development.…”

ATP-dependent chromatin remodeling during mammalian development

“…Both SNF2H-and SNF2L-containing complexes are also essential during the development of ectoderm-derived lineages (Alvarez-Saavedra et al, 2014;Barak et al, 2003;Koludrovic et al, 2015;Yip et al, 2012). During nervous system development (Fig.…”