A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation

Genes & Development
Kulwant SinghDidier Trono

Abstract

The transcriptional activator MyoD serves as a master controller of myogenesis. Often in partnership with Mef2 (myocyte enhancer factor 2), MyoD binds to the promoters of hundreds of muscle genes in proliferating myoblasts yet activates these targets only upon receiving cues that launch differentiation. What regulates this off/on switch of MyoD function has been incompletely understood, although it is known to reflect the action of chromatin modifiers. Here, we identify KAP1 (KRAB [Krüppel-like associated box]-associated protein 1)/TRIM28 (tripartite motif protein 28) as a key regulator of MyoD function. In myoblasts, KAP1 is present with MyoD and Mef2 at many muscle genes, where it acts as a scaffold to recruit not only coactivators such as p300 and LSD1 but also corepressors such as G9a and HDAC1 (histone deacetylase 1), with promoter silencing as the net outcome. Upon differentiation, MSK1-mediated phosphorylation of KAP1 releases the corepressors from the scaffold, unleashing transcriptional activation by MyoD/Mef2 and their positive cofactors. Thus, our results reveal KAP1 as a previously unappreciated interpreter of cell signaling, which modulates the ability of MyoD to drive myogenesis.

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Citations

Apr 9, 2016·Journal of Molecular Biology·Valentine BattistiVéronique Joliot
Jul 5, 2016·Frontiers in Cell and Developmental Biology·Kathleen M S E Reyskens, J Simon C Arthur
Jul 19, 2016·Cell Stem Cell·Thorold W TheunissenRudolf Jaenisch
Aug 24, 2016·Skeletal Muscle·Biswanath ChatterjeeAsoke K Mal
Jan 15, 2016·Cold Spring Harbor Symposia on Quantitative Biology·Didier Trono
Apr 4, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Marco CassanoDidier Trono
Feb 23, 2019·Cell Death & Disease·Yutong SuiGuangyu Li
Feb 19, 2020·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Annamaria KauzlaricDidier Trono
Apr 18, 2015·The Journal of Biological Chemistry·Woo Jae KimDaniel A Haber
Jun 9, 2017·FEBS Open Bio·Chris J HunterJ Simon C Arthur
Jun 30, 2018·Nucleic Acids Research·Suk Min JangDidier Trono
Oct 30, 2020·Andrologia·Mahzad NasirshalalPegah Ghandil
Jan 13, 2021·Skeletal Muscle·Jimmy MassenetF Jeffrey Dilworth
Sep 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·Neeraj AgarwalDan Theodorescu

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