Acetylation reprograms MITF target selectivity and residence time

Pakavarin Louphrasitthiphol, Alessia Loffreda, Vivian Pogenberg, Sarah Picaud, Alexander Schepsky, Hans Friedrichsen, Zhiqiang Zeng, Anahita Lashgari, Benjamin Thomas, E. Elizabeth Patton, Matthias Wilmanns, Panagis Filippakopoulos, Jean-Philippe Lambert, Eiríkur Steingrímsson, Davide Mazza and Colin R. Goding ()
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Pakavarin Louphrasitthiphol: University of Oxford, Headington
Alessia Loffreda: Ospedale San Raffaele
Vivian Pogenberg: European Molecular Biology Laboratory, Hamburg Unit
Sarah Picaud: University of Oxford, Headington
Alexander Schepsky: University of Oxford, Headington
Hans Friedrichsen: University of Oxford, Headington
Zhiqiang Zeng: MRC Human Genetics Unit & Edinburgh Cancer Research Centre
Anahita Lashgari: CHU de Québec – Université Laval Research Center
Benjamin Thomas: University of Oxford
E. Elizabeth Patton: MRC Human Genetics Unit & Edinburgh Cancer Research Centre
Matthias Wilmanns: European Molecular Biology Laboratory, Hamburg Unit
Panagis Filippakopoulos: University of Oxford, Headington
Jean-Philippe Lambert: CHU de Québec – Université Laval Research Center
Eiríkur Steingrímsson: University of Iceland
Davide Mazza: Ospedale San Raffaele
Colin R. Goding: University of Oxford, Headington

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41793-7

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