Transcriptional coactivator MED15 is required for beta cell maturation
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.
Authors
- Samantha Mar (ORCID: https://orcid.org/0000-0003-0215-6052)
- Shannon L. J. Sproul (ORCID: https://orcid.org/0000-0002-3014-6575)
- Xuanjin Cheng (ORCID: https://orcid.org/0000-0002-2119-1788)
- Francis C. Lynn (ORCID: https://orcid.org/0000-0001-9318-1063)
- Rocky Shi
- Katarina Zosel (ORCID: https://orcid.org/0009-0002-5154-8343)
- Eric E. Xu (ORCID: https://orcid.org/0000-0003-3399-2184)
- Stefan Taubert (ORCID: https://orcid.org/0000-0002-2432-7257)
- Shugo Sasaki (ORCID: https://orcid.org/0000-0002-3696-7809)
- Thilo Speckmann (ORCID: https://orcid.org/0000-0001-7265-0879)
- Dan S. Luciani (ORCID: https://orcid.org/0000-0002-4318-4159)
- Robyn Cullen
- Ben Vanderkruk (ORCID: https://orcid.org/0000-0002-0606-0376)
- Alex Z. Kadhim
- Cuilan Nian
- Bradford G. Hoffman
- Meixia Dan
- Rachel J. Spencer
Institutions
- University of British Columbia (CA)
- BC Children's Hospital (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-08
- DOI
- https://doi.org/10.1038/s41467-024-52801-9
- Citations
- 5
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 2.86
Funders
- Juvenile Diabetes Research Foundation United States of America
- Regeneron Pharmaceuticals
- BC Children's Hospital
- Diabetes Canada
- Michael Smith Health Research BC
- National Institutes of Health
- University of California, Davis
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada