Acetylation reprograms MITF target selectivity and residence time.
Acetylation reprograms MITF target selectivity and residence time.
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DOI：
10.1038/s41467-023-41793-7
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发表时间：
2023-09-28
影响因子：
16.6
通讯作者：
Goding, Colin R.
中科院分区：
文献类型：
--
作者：
Louphrasitthiphol, Pakavarin;Loffreda, Alessia;Pogenberg, Vivian;Picaud, Sarah;Schepsky, Alexander;Friedrichsen, Hans;Zeng, Zhiqiang;Lashgari, Anahita;Thomas, Benjamin;Patton, E. Elizabeth;Wilmanns, Matthias;Filippakopoulos, Panagis;Lambert, Jean-Philippe;Steingrimsson, Eirikur;Mazza, Davide;Goding, Colin R.
转录因子区分与特定生物学功能相关的不同类型结合位点的能力是发育和稳态中有效基因调控的基础。如何做到这一点，人们知之甚少。小眼症相关转录因子MITF是一种在黑素细胞发育和黑色素瘤中起关键作用的谱系存活癌基因。MITF抑制侵袭，重新编程代谢，促进增殖和分化。MITF如何区分分化和增殖相关靶点尚不清楚。在这里，我们表明，与许多转录因子相比，MITF表现出很长的停留时间，这是减少了p300/CBP介导的MITF乙酰化K206。虽然K206乙酰化也降低了全基因组MITF DNA结合亲和力，但它优先引导DNA结合远离分化相关的CATGTG基序，朝向CACGTG元件。结果揭示了抑制分化的乙酰化介导的开关，并提供了为什么人类K206 Q MITF突变与Waardenburg综合征相关的机制解释。小眼症相关转录因子MITF是一种在黑素细胞发育和黑色素瘤中起关键作用的谱系存活癌基因。在这里，作者揭示了MITF具有非常长的染色质结合半衰期，并且MITF靶向选择性受K206乙酰化调节，K206乙酰化是与Waardenburg综合征相关的残基。
The ability of transcription factors to discriminate between different classes of binding sites associated with specific biological functions underpins effective gene regulation in development and homeostasis. How this is achieved is poorly understood. The microphthalmia-associated transcription factor MITF is a lineage-survival oncogene that plays a crucial role in melanocyte development and melanoma. MITF suppresses invasion, reprograms metabolism and promotes both proliferation and differentiation. How MITF distinguishes between differentiation and proliferation-associated targets is unknown. Here we show that compared to many transcription factors MITF exhibits a very long residence time which is reduced by p300/CBP-mediated MITF acetylation at K206. While K206 acetylation also decreases genome-wide MITF DNA-binding affinity, it preferentially directs DNA binding away from differentiation-associated CATGTG motifs toward CACGTG elements. The results reveal an acetylation-mediated switch that suppresses differentiation and provides a mechanistic explanation of why a human K206Q MITF mutation is associated with Waardenburg syndrome. The microphthalmia-associated transcription factor MITF is a lineage-survival oncogene that plays a crucial role in melanocyte development and melanoma. Here, the authors reveal that MITF has a very long chromatin-bound half-life, and that MITF target selectivity is regulated by K206 acetylation, a residue linked to Waardenburg syndrome.
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