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Ludwig Oxford’s Colin Goding and his lab reveal an acetylation-mediated switch that suppresses differentiation and provides an explanation of why a human K206Q MITF mutation is associated with Waardenburg syndrome.

The microphthalmia-associated transcription factor (MITF) is the master regulator of pigment cell development and plays crucial roles in melanoma (a form of skin cancer) progression and drug resistance as a lineage survival oncogene. How MITF distinguishes between its seemingly incompatible differentiation and proliferation-associated targets is unknown, and the Goding group at Oxford has identified an acetylation-mediated switch that preferentially suppress MITF binding to differentiation-associated genes.

Pakavarin Louphrasitthiphol and co-workers have shown that the ability of MITF to bind DNA is inhibited by CBP/p300-mediated acetylation of K206. The results, discussed further in Nature Communications, reveal a surprising finding that, unlike the typical residence time of few seconds for most transcription factors, over 40% of MITF molecules are tightly bound within the nucleus with residence times of over 100 seconds. This is comparable to transcriptional repressor CTCF and polycomb repressive complex 1 PRC1 and suggests that MITF might play similar roles in establishment and maintenance of chromatin organisation specific to the melanocyte lineage.

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