Year: 2023
Type: article
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.
Source: Nature Communications
Authors: 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, Colin R. Goding
Institutions: University of Tsukuba, University of Oxford, Ludwig Cancer Research, IRCCS Ospedale San Raffaele, Universität Hamburg, University Medical Center Hamburg-Eppendorf, European Molecular Biology Laboratory, European Molecular Biology Laboratory, University of Iceland, Edinburgh Cancer Research, Institute of Genetics and Cancer, MRC Human Genetics Unit, Université Laval, Centre de recherche du CHU de Québec-Université Laval, CHU de Québec-Université Laval, Vita-Salute San Raffaele University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: Melanoma Research Alliance, Cancer Research Society, Ludwig Institute for Cancer Research, Wellcome Trust, Cancer Research UK, Rosetrees Trust, Associazione Italiana per la Ricerca sul Cancro, Háskóli Íslands, Fondazione Italiana per la Ricerca sul Cancro, National Institutes of Health, Medical Research Council, RIKEN, National Cancer Institute
Awards: G156594879, G3270971059, Imaging and targeting dormant and pro-metastatic melanoma lesions in vivo, G4844238699, ZMYND8-regulation of MITF as potential therapeutic target in melanoma, G5520316217, Targeting developmental cell states in melanoma, Gene-drug interactions in the melanocyte lineage and melanoma, The integrated stress response and the microenvironment in melanoma progression, G7320435082, G8324731452, G9000022318, G9000157923
OpenAlex ID: W4387134972