Transcriptional coactivator MED15 is required for beta cell maturation
Alex Z Kadhim1,2,3, Ben Vanderkruk1,4, Samantha Mar1,4
1Diabetes Research Program, BC Children's Hospital Research Institute, Vancouver, Canada.
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.
Insights
Mediator subunit MED15 is crucial for pancreatic beta-cell maturation. Its absence impairs development, while its presence enhances maturation markers, suggesting a conserved role in diabetes research.
Area of Science:
- Molecular Biology
- Endocrinology
- Developmental Biology
Background:
- Mediator complex regulates RNA Polymerase II activity and interacts with transcription factors.
- Reduced MED15 expression is observed in pancreatic islets of individuals with type 2 diabetes.
- Understanding MED15's role is vital for beta-cell function and diabetes research.
Purpose of the Study:
- To investigate the function of MED15 in pancreatic beta-cell development and maturation.
- To elucidate how MED15 and the Mediator complex control gene expression in beta-cells.
- To explore the conserved role of MED15 in human beta-like cell development.
Main Methods:
- Analysis of Med15 expression during mouse beta-cell development.
- Generation of Med15 knockout mouse models for beta-cell studies.
- Chromatin immunoprecipitation sequencing (ChIP-seq) and co-immunoprecipitation (Co-IP) to identify protein interactions.
- Engineering human embryonic stem cell-derived beta-like cells to assess MED15's effect.
Main Results:
- Med15 is expressed during mouse beta-cell development and maturation.
- Med15 knockout in mouse beta-cells leads to maturation defects but not changes in cell mass or insulin expression.
- Med15 interacts with transcription factors Nkx6-1 and NeuroD1 to regulate beta-cell maturation genes.
- Enhanced MED15 expression in human beta-like cells increases maturation markers, indicating a conserved role.
Conclusions:
- Mediator subunit MED15 plays a conserved role in beta-cell maturation.
- MED15 influences beta-cell maturation by modulating transcription factor function.
- These findings offer insights into beta-cell function and potential therapeutic targets for diabetes.
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