1. Transcriptional coactivator MED15 is required for beta cell maturation.
- Author
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Kadhim AZ, Vanderkruk B, Mar S, Dan M, Zosel K, Xu EE, Spencer RJ, Sasaki S, Cheng X, Sproul SLJ, Speckmann T, Nian C, Cullen R, Shi R, Luciani DS, Hoffman BG, Taubert S, and Lynn FC
- Subjects
- Animals, Humans, Mice, Cell Differentiation, Male, Female, Nerve Tissue Proteins metabolism, Nerve Tissue Proteins genetics, Insulin metabolism, Adult, Human Embryonic Stem Cells metabolism, Human Embryonic Stem Cells cytology, Mice, Inbred C57BL, Insulin-Secreting Cells metabolism, Mediator Complex metabolism, Mediator Complex genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Mice, Knockout, Homeodomain Proteins metabolism, Homeodomain Proteins genetics, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 genetics
- 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., (© 2024. The Author(s).)
- Published
- 2024
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