GSE137776
Acetylation reprograms MITF target selectivity and residence time
Key to effective gene regulation in development and homeostasis is the ability of transcription factors to discriminate between different classes of binding sites. Yet how this is achieved is poorly understood. The microphthalmia-associated transcription factor MITF is a lineage-survival oncogene that plays a crucial role in melanoma and melanocyte development where it suppresses invasion but promotes both proliferation and differentiation. How MITF distinguishes between differentiation and proliferation-associated targets is unknown. Unexpectedly we show here that differentiation-associated target genes are characterized by low affinity MITF binding sites. MAPK signaling, a key driver of melanomagenesis downstream from BRAF and NRAS, promotes p300/CBP-mediated MITF acetylation at K206 to reduce preferentially DNA binding affinity at differentiation-associated targets. The results reveal a MAPK-driven acetylation switch that can trigger de-differentiation of melanocytes and provide a mechanistic explanation of why a human K206Q MITF mutation is associated with Waardenburg's syndrome characterized by pigmentation abnormalities. Overall design: 501mel melanoma cell lines engineered to express ectopic-doxycycline-inducible-HA-epitope-tag-murine Mitf-WT or K206Q or K206R were treated with 20ng Dox prior to fixation and ChIP-sequencing