Chromatin-Remodelling Complex NURF Is Essential for Differentiation of Adult Melanocyte Stem Cells.
Chromatin-Remodelling Complex NURF Is Essential for Differentiation of Adult Melanocyte Stem Cells.
复制标题
DOI：
10.1371/journal.pgen.1005555
复制
发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Davidson I
中科院分区：
文献类型：
--
作者：
Koludrovic D;Laurette P;Strub T;Keime C;Le Coz M;Coassolo S;Mengus G;Larue L;Davidson I
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. 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. At each angen phase, 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 Factor (MITF) the master regulator of the melanocyte lineage. We show that MITF associates with the NURF chromatin-remodelling factor in melanoma cells. NURF acts downstream of MITF in melanocytes and melanoma cells co-regulating gene expression in vitro. In vivo, mice lacking the NURF subunit Bptf in the melanocyte lineage show premature greying as they are unable to generate mature melanocytes from the adult stem cell population. We find that the melanocyte stem cells from these animals are abnormal and that once they are stimulated at anagen, Bptf is required to ensure the expression of melanocyte markers and their differentiation into mature adult melanocytes. Chromatin remodelling by NURF therefore appears to be essential for the transition of the transcriptionally quiescent stem cell to the differentiated state.
