Transcriptional coactivator MED15 is required for beta cell maturation

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, Robyn Cullen, Rocky Shi, Dan S. Luciani, Bradford G. Hoffman, Stefan Taubert () and Francis C. Lynn ()
Additional contact information
Alex Z. Kadhim: BC Children’s Hospital Research Institute
Ben Vanderkruk: BC Children’s Hospital Research Institute
Samantha Mar: BC Children’s Hospital Research Institute
Meixia Dan: BC Children’s Hospital Research Institute
Katarina Zosel: BC Children’s Hospital Research Institute
Eric E. Xu: BC Children’s Hospital Research Institute
Rachel J. Spencer: BC Children’s Hospital Research Institute
Shugo Sasaki: BC Children’s Hospital Research Institute
Xuanjin Cheng: University of British Columbia
Shannon L. J. Sproul: BC Children’s Hospital Research Institute
Thilo Speckmann: BC Children’s Hospital Research Institute
Cuilan Nian: BC Children’s Hospital Research Institute
Robyn Cullen: University of British Columbia
Rocky Shi: BC Children’s Hospital Research Institute
Dan S. Luciani: BC Children’s Hospital Research Institute
Bradford G. Hoffman: BC Children’s Hospital Research Institute
Stefan Taubert: BC Children’s Hospital Research Institute
Francis C. Lynn: BC Children’s Hospital Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52801-9

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