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Transcriptional co-regulator Med15 is required to maintain functional maturation in adult β-cells

ABSTRACT: Transcriptional coregulators, such as the Mediator complex, partner with transcription factors to regulate gene transcription throughout all stages of life. Subunit Med15 is required for pre-natal development and post-natal maturation of pancreatic β-cells. However, whether Med15 continues to play a role in β-cell function after maturation is complete, and throughout adulthood, is unknown. To investigate the role of Med15 in β-cells post-maturation, we induced a β-cell specific Med15 knockout at six weeks age in male and female mice. Ablation of Med15 led to glucose intolerance and impaired insulin secretion. RNA-sequencing revealed downregulation of β-cell maturation markers. Further, we implanted insulin pellets into knockout mice to lower blood glucose and performed RNA-seq to validate that the transcriptional changes were a direct consequence of the Med15 loss and not due to hyperglycemia in the knockout mice. This study shows that Med15 is required after weaning and throughout life to maintain functional β-cell maturity.

ORGANISM(S): Mus musculus

PROVIDER: GSE343956 | GEO | 2026/08/19

REPOSITORIES: GEO

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Project description:The lower glucose-responsiveness of neonatal beta cells is generally considered a sign of endocrine immaturity. We compared mRNA profiles of neonatal and 10-weeks old rat beta cells to see how their gene expression changes with functional maturation. Neonatal beta cells showed a lower glucose-inducible increment in insulin production than adult cells. This was in part explained by basal protein synthetic hyperactivity of neonatal cells: while at 2.5mM glucose 80% of neonatal beta cells were recruited into active protein synthesis, 10 mM glucose was required to achieve a similar fraction of active adult beta cells. Besides this progressive recruitment, glucose exerted in both age groups an additional amplifying effect in the recruited cells, but clearly more so in adult beta cells that showed a higher maximal synthetic capacity/cell. Neonatal beta cells balanced an advanced endocrine differentiation as judged by their mRNA expression of conserved beta cell marker genes, with higher expression of genes involved in cell cycle and development. One example, Delta-like 1 homolog (DLK1) was used to investigate if neonatal beta cells with basal hyperactivity corresponded to a more immature subset, as marked by high DLK1. Neonatal pancreas contained distinct subsets of DLK1high and DLK1low insulin-expressing cells, but both showed equal hyperactivity. We conclude that neonatal beta cells combine advanced endocrine maturation with traits of residual developmental immaturity. If DLK1 is used as marker for the latter, the basal hyperactivity which proved to be a cardinal feature of neonatal beta cells is not a direct reflection of their residual immaturity. A genome-wide view on postnatal maturation/differentiation of the rat beta cells The study compares Affymetrix RG230.20 expression profiles of 3 cell subsets: (1) HSSC: a population of cells isolated from post natal day 2-3 rat pancreas that is enriched (65-70%) in insulin cells (n=3), (2) LSSC: a population of cells isolated from postnatal day 2-3 rat pancreas that is mostly devoid of endocrine cells, and selected by its low side scatter (n=3); and (3) adult beta: a reference population of FACS-purified adult rat beta cells (>90% insulin+) freshly isolated from pancreas of 10 weeks-old rats (n=5). RNA was extracted from the cells immediately after isolation, without further treatment or culture. Details of the isolation procedure and extensive microscopic characterization of the preps are described in the accompanying scientific paper by Martens GA et al.

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Transcriptional co-regulator Med15 is required to maintain functional maturation in adult β-cells

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