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Transcriptional coactivator MED15 is required for beta cell maturation

Author

Listed:
  • Alex Z. Kadhim

    (BC Children’s Hospital Research Institute
    University of British Columbia
    University of British Columbia)

  • Ben Vanderkruk

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Samantha Mar

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Meixia Dan

    (BC Children’s Hospital Research Institute
    University of British Columbia
    University of British Columbia)

  • Katarina Zosel

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Eric E. Xu

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Rachel J. Spencer

    (BC Children’s Hospital Research Institute
    University of British Columbia
    University of British Columbia)

  • Shugo Sasaki

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Xuanjin Cheng

    (University of British Columbia)

  • Shannon L. J. Sproul

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Thilo Speckmann

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Cuilan Nian

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Robyn Cullen

    (University of British Columbia)

  • Rocky Shi

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Dan S. Luciani

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Bradford G. Hoffman

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Stefan Taubert

    (BC Children’s Hospital Research Institute
    University of British Columbia
    University of British Columbia)

  • Francis C. Lynn

    (BC Children’s Hospital Research Institute
    University of British Columbia
    University of British Columbia)

Abstract

Mediator, a co-regulator complex required for RNA Polymerase II activity, interacts with tissue-specific transcription factors to regulate development and maintain homeostasis. We observe reduced Mediator subunit MED15 expression in endocrine hormone-producing pancreatic islets isolated from people living with type 2 diabetes and sought to understand how MED15 and Mediator control gene expression programs important for the function of insulin-producing β-cells. Here we show that Med15 is expressed during mouse β-cell development and maturation. Knockout of Med15 in mouse β-cells causes defects in β-cell maturation without affecting β-cell mass or insulin expression. ChIP-seq and co-immunoprecipitation analyses found that Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 to regulate key β-cell maturation genes. In support of a conserved role during human development, human embryonic stem cell-derived β-like cells, genetically engineered to express high levels of MED15, express increased levels of maturation markers. We provide evidence of a conserved role for Mediator in β-cell maturation and demonstrate an additional layer of control that tunes β-cell transcription factor function.

Suggested Citation

  • Alex Z. Kadhim & Ben Vanderkruk & Samantha Mar & Meixia Dan & Katarina Zosel & Eric E. Xu & Rachel J. Spencer & Shugo Sasaki & Xuanjin Cheng & Shannon L. J. Sproul & Thilo Speckmann & Cuilan Nian & Ro, 2024. "Transcriptional coactivator MED15 is required for beta cell maturation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52801-9
    DOI: 10.1038/s41467-024-52801-9
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    References listed on IDEAS

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