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pH-controlled histone acetylation amplifies melanocyte differentiation downstream of MITF.
EMBO Reports ( IF 6.5 ) Pub Date : 2019-11-11 , DOI: 10.15252/embr.201948333 Desingu Ayyappa Raja 1, 2 , Vishvabandhu Gotherwal 1, 2 , Shaunak A Burse 1, 2 , Yogaspoorthi J Subramaniam 1, 2 , Farina Sultan 1, 2 , Archana Vats 1 , Hemlata Gautam 1 , Babita Sharma 1, 2 , Sachin Sharma 1, 2 , Archana Singh 1, 2 , Sridhar Sivasubbu 1 , Rajesh S Gokhale 1 , Vivek T Natarajan 1, 2
EMBO Reports ( IF 6.5 ) Pub Date : 2019-11-11 , DOI: 10.15252/embr.201948333 Desingu Ayyappa Raja 1, 2 , Vishvabandhu Gotherwal 1, 2 , Shaunak A Burse 1, 2 , Yogaspoorthi J Subramaniam 1, 2 , Farina Sultan 1, 2 , Archana Vats 1 , Hemlata Gautam 1 , Babita Sharma 1, 2 , Sachin Sharma 1, 2 , Archana Singh 1, 2 , Sridhar Sivasubbu 1 , Rajesh S Gokhale 1 , Vivek T Natarajan 1, 2
Affiliation
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Tanning response and melanocyte differentiation are mediated by the central transcription factor MITF. This involves the rapid and selective induction of melanocyte maturation genes, while concomitantly the expression of other effector genes is maintained. In this study, using cell-based and zebrafish model systems, we report on a pH-mediated feed-forward mechanism of epigenetic regulation that enables selective amplification of the melanocyte maturation program. We demonstrate that MITF activation directly elevates the expression of the enzyme carbonic anhydrase 14 (CA14). Nuclear localization of CA14 leads to an increase of the intracellular pH, resulting in the activation of the histone acetyl transferase p300/CBP. In turn, enhanced H3K27 histone acetylation at selected differentiation genes facilitates their amplified expression via MITF. CRISPR-mediated targeted missense mutation of CA14 in zebrafish results in the formation of immature acidic melanocytes with decreased pigmentation, establishing a central role for this mechanism during melanocyte differentiation in vivo. Thus, we describe an epigenetic control system via pH modulation that reinforces cell fate determination by altering chromatin dynamics.
中文翻译：
pH 控制的组蛋白乙酰化可放大 MITF 下游的黑素细胞分化。
晒黑反应和黑素细胞分化是由中央转录因子 MITF 介导的。这涉及快速且选择性地诱导黑素细胞成熟基因，同时维持其他效应基因的表达。在这项研究中，我们使用基于细胞和斑马鱼的模型系统，报告了 pH 介导的表观遗传调控前馈机制，该机制能够选择性放大黑素细胞成熟程序。我们证明 MITF 激活可直接提高碳酸酐酶 14 (CA14) 的表达。 CA14 的核定位导致细胞内 pH 值升高，从而激活组蛋白乙酰转移酶 p300/CBP。反过来，选定分化基因上 H3K27 组蛋白乙酰化的增强可通过 MITF 促进其扩增表达。斑马鱼中 CRISPR 介导的 CA14 靶向错义突变导致形成不成熟的酸性黑素细胞，色素沉着减少，确立了这种机制在体内黑素细胞分化过程中的核心作用。因此，我们描述了一种通过 pH 调节的表观遗传控制系统，该系统通过改变染色质动力学来加强细胞命运的决定。
更新日期：2020-01-07
中文翻译：
pH 控制的组蛋白乙酰化可放大 MITF 下游的黑素细胞分化。
晒黑反应和黑素细胞分化是由中央转录因子 MITF 介导的。这涉及快速且选择性地诱导黑素细胞成熟基因，同时维持其他效应基因的表达。在这项研究中，我们使用基于细胞和斑马鱼的模型系统，报告了 pH 介导的表观遗传调控前馈机制，该机制能够选择性放大黑素细胞成熟程序。我们证明 MITF 激活可直接提高碳酸酐酶 14 (CA14) 的表达。 CA14 的核定位导致细胞内 pH 值升高，从而激活组蛋白乙酰转移酶 p300/CBP。反过来，选定分化基因上 H3K27 组蛋白乙酰化的增强可通过 MITF 促进其扩增表达。斑马鱼中 CRISPR 介导的 CA14 靶向错义突变导致形成不成熟的酸性黑素细胞，色素沉着减少，确立了这种机制在体内黑素细胞分化过程中的核心作用。因此，我们描述了一种通过 pH 调节的表观遗传控制系统，该系统通过改变染色质动力学来加强细胞命运的决定。
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