Epigenetic and pharmacological control of pigmentation via Bromodomain Protein 9 (BRD9).
Epigenetic and pharmacological control of pigmentation via Bromodomain Protein 9 (BRD9).
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DOI：
10.1111/pcmr.13068
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发表时间：
2023-01
影响因子：
4.3
通讯作者：
de la Serna, Ivana L.
中科院分区：
文献类型：
--
作者：
Basuroy, Tupa;Dreier, Megan;Baum, Caitlin;Blomquist, Thomas;Trumbly, Robert;Filipp, Fabian, V;de la Serna, Ivana L.
关键词：
谱系特异性分化程序是由染色质结构的表观遗传变化激活的。产生黑色素的黑色素细胞维持一个基因表达程序，确保代谢产物转化为色素、黑色素并转移到周围细胞。在神经外胚层发育过程中，开关/糖不可发酵（SWI/SNF）染色质重塑复合物的催化亚基SMARCA4 （BRG1）对谱系鉴定至关重要。SMARCA4也是多能神经嵴前体发育为黑色素母细胞所必需的，黑色素母细胞分化为产生色素的黑色素细胞。除了催化结构域外，SMARCA4和几个SWI/SNF亚基还含有可被药物抑制的溴结构域。我们研究了SWI/SNF溴结构域的药理抑制剂对黑素细胞分化的影响。引人注目的是，用选定的溴结构域抑制剂处理小鼠黑色素母细胞和人类新生儿表皮黑色素细胞，可以消除黑色素合成和可见的色素沉着。利用功能基因组学，研究人员发现BRD9的溴域小分子选择性iBRD9可以抑制色素沉着特异性基因的表达。BRD9的缺失证实了在黑色素母细胞向黑色素细胞和黑色素瘤细胞的分化过程中，色素沉着基因的表达是必需的。染色质免疫沉淀试验显示，iBRD9破坏了BRD9和催化亚基SMARCA4在黑素细胞特异性位点的占据。这些数据表明BRD9促进黑素细胞色素沉着，而BRD9的药理学抑制是抑制性的。
Lineage‐specific differentiation programs are activated by epigenetic changes in chromatin structure. Melanin‐producing melanocytes maintain a gene expression program ensuring appropriate enzymatic conversion of metabolites into the pigment, melanin, and transfer to surrounding cells. During neuroectodermal development, SMARCA4 (BRG1), the catalytic subunit of SWItch/Sucrose Non‐Fermentable (SWI/SNF) chromatin remodeling complexes, is essential for lineage specification. SMARCA4 is also required for development of multipotent neural crest precursors into melanoblasts, which differentiate into pigment‐producing melanocytes. In addition to the catalytic domain, SMARCA4 and several SWI/SNF subunits contain bromodomains which are amenable to pharmacological inhibition. We investigated the effects of pharmacological inhibitors of SWI/SNF bromodomains on melanocyte differentiation. Strikingly, treatment of murine melanoblasts and human neonatal epidermal melanocytes with selected bromodomain inhibitors abrogated melanin synthesis and visible pigmentation. Using functional genomics, iBRD9, a small molecule selective for the bromodomain of BRD9 was found to repress pigmentation‐specific gene expression. Depletion of BRD9 confirmed a requirement for expression of pigmentation genes in the differentiation program from melanoblasts into pigmented melanocytes and in melanoma cells. Chromatin immunoprecipitation assays showed that iBRD9 disrupts the occupancy of BRD9 and the catalytic subunit SMARCA4 at melanocyte‐specific loci. These data indicate that BRD9 promotes melanocyte pigmentation whereas pharmacological inhibition of BRD9 is repressive.
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影响因子：
4.5
作者：
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
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--
影响因子：
16.6
作者：
Gatchalian J;Malik S;Ho J;Lee DS;Kelso TWR;Shokhirev MN;Dixon JR;Hargreaves DC
通讯作者：
Hargreaves DC
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14.9
作者：
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通讯作者：
Yamanishi Y
影响因子：
7.3
作者：
Karim RM;Chan A;Zhu JY;Schönbrunn E
通讯作者：
Schönbrunn E