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Acetylation reprograms MITF target selectivity and residence time

Author

Listed:
  • Pakavarin Louphrasitthiphol

    (University of Oxford, Headington
    University of Tsukuba)

  • Alessia Loffreda

    (Ospedale San Raffaele)

  • Vivian Pogenberg

    (European Molecular Biology Laboratory, Hamburg Unit
    University Hamburg Medical Centre Hamburg-Eppendorf)

  • Sarah Picaud

    (University of Oxford, Headington)

  • Alexander Schepsky

    (University of Oxford, Headington
    University of Iceland)

  • 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
    University Hamburg Medical Centre Hamburg-Eppendorf)

  • 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
    Università Vita-Salulte San Raffaele)

  • Colin R. Goding

    (University of Oxford, Headington)

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.

Suggested Citation

  • Pakavarin Louphrasitthiphol & Alessia Loffreda & Vivian Pogenberg & Sarah Picaud & Alexander Schepsky & Hans Friedrichsen & Zhiqiang Zeng & Anahita Lashgari & Benjamin Thomas & E. Elizabeth Patton & M, 2023. "Acetylation reprograms MITF target selectivity and residence time," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41793-7
    DOI: 10.1038/s41467-023-41793-7
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    References listed on IDEAS

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