A chemical modification makes MITF switch genomic targets
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.