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A chemical modification makes MITF switch genomic targets

Pakavarin Louphrasitthiphol, Ludwig Cancer Research Oxford
Pakavarin Louphrasitthiphol
Colin Goding, Ludwig Cancer Research Oxford
Colin Goding

The microphthalmia-associated transcription factor (MITF) is the master regulator of pigment cell, or melanocyte, development. As a lineage survival oncogene, it plays a crucial role in the skin cancer melanoma and its resistance to therapy. How MITF distinguishes between its seemingly incompatible differentiation and proliferation-associated targets in the genome has been a bit of a puzzle. Ludwig Oxford’s Pakavarin Louphrasitthiphol, Colin Goding and colleagues discovered that the ability of MITF to bind DNA is inhibited by CBP/p300-mediated acetylation of its lysine residue 206, which preferentially directs MITF binding away from DNA elements involved in differentiation. This may explain why a mutation of that residue—K206Q—is associated with Waardenburg syndrome, a congenital disorder often characterized by defects in pigmentation of hair, skin and eyes. Reported in a September issue of Nature Communications, the findings also reveal that more than 40% of MITF molecules are tightly bound to DNA, with residence times of over 100 seconds—compared to just a handful of seconds for most transcription factors. This makes MITF comparable to transcriptional repressor CTCF and polycomb repressive complex 1 (PRC1) and suggests that it might play similar roles in the establishment and maintenance of chromatin organization specific to the melanocyte lineage.

Acetylation reprograms MITF target selectivity and residence time
Nature Communications, 2023 September 28

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