TY - JOUR
T1 - Acetylation reprograms MITF target selectivity and residence time
AU - Louphrasitthiphol, Pakavarin
AU - Loffreda, Alessia
AU - Pogenberg, Vivian
AU - Picaud, Sarah
AU - Schepsky, Alexander
AU - Friedrichsen, Hans
AU - Zeng, Zhiqiang
AU - Lashgari, Anahita
AU - Thomas, Benjamin
AU - Patton, E. elizabeth
AU - Wilmanns, Matthias
AU - Filippakopoulos, Panagis
AU - Lambert, Jean-Philippe
AU - Steingrímsson, Eiríkur
AU - Mazza, Davide
AU - Goding, Colin r.
N1 - Funding Information:
The Piggybac vectors were kindly provided by Kazuhiro Murakami (RIKEN, Kobe, Japan). This work was funded by the Ludwig Institute for Cancer Research (C.R.G.); Cancer Research UK (CRUK) grant number C38302/A12981, through a CRUK Oxford Centre Prize DPhil Studentship (H.F.); The Medical Research Council grants MR/N010051/1 (P.F.) and MC_UU_00007/9 (Z.Z., E.E.P.); L’Oreal-Melanoma Research Alliance 401181 (E.E.P.); The Wellcome Trust and The Postdoc Fund of the University of Iceland (A.S.); The Research Fund of Iceland (E.S.); a European Research Consolidator Award ZF-MEL-CHEMBIO 648489 (E.E.P.); NIH R01 CA268597-01 (C.R.G., PL); the Italian Foundation for Cancer Research AIRC IG-2018-ID21897 (D.M., A.Lo); A Fonds de Recherche du Québec-Santé Junior 2 salary award (J.-P.L.) and a Cancer Research Society operating grant (935296) to J.-P.L. (A.La).
Funding Information:
The Piggybac vectors were kindly provided by Kazuhiro Murakami (RIKEN, Kobe, Japan). This work was funded by the Ludwig Institute for Cancer Research (C.R.G.); Cancer Research UK (CRUK) grant number C38302/A12981, through a CRUK Oxford Centre Prize DPhil Studentship (H.F.); The Medical Research Council grants MR/N010051/1 (P.F.) and MC_UU_00007/9 (Z.Z., E.E.P.); L’Oreal-Melanoma Research Alliance 401181 (E.E.P.); The Wellcome Trust and The Postdoc Fund of the University of Iceland (A.S.); The Research Fund of Iceland (E.S.); a European Research Consolidator Award ZF-MEL-CHEMBIO 648489 (E.E.P.); NIH R01 CA268597-01 (C.R.G., PL); the Italian Foundation for Cancer Research AIRC IG-2018-ID21897 (D.M., A.Lo); A Fonds de Recherche du Québec-Santé Junior 2 salary award (J.-P.L.) and a Cancer Research Society operating grant (935296) to J.-P.L. (A.La).
Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/9/28
Y1 - 2023/9/28
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-023-41793-7
DO - 10.1038/s41467-023-41793-7
M3 - Article
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -