Pancreatic β-cells play a central role in regulating glucose homeostasis. One prominent regulator of both β-cell fate and function is Glis3, a transcription factor with both co-activating and co-repressive roles. Both humans and mice lacking a functional copy of Glis3 are diabetic from birth, with a near complete absence of β-cells. Interestingly, Glis3 is expressed relatively early during pancreas development prior to the differentiation of ductal and endocrine cells from a common lineage, and is maintained in both β-cells as well as ductal cells. Furthermore, postnatal deletion of Glis3 also results in hyperglycemia, suggesting Glis3 as a critical regulator of postnatal β-cell function as well. Yet, while much is known about the phenotype of Glis3 deletions, little is known about its molecular function.

My research focuses on how Glis3 regulates β-cell development and function. To determine which genes are regulated by Glis3, a mouse model with a pancreas-specific deletion of Glis3 was utilized. RNA-seq analysis of isolated islets revealed a large number of both upregulated and downregulated genes, and ChIP-seq analysis of Glis3 in islets revealed many of these genes are direct targets of Glis3 regulation. Interestingly, Glis3 binding largely overlaps with binding of the transcription factor Nkx6.1, and partially overlaps with transcription factors Pdx1 and Nkx2.2, but shows less overlap with other islet-enriched transcription factors. This indicates that Glis3 could function in distinct regulatory complexes, and that better understanding of Glis3 gene regulation within the pancreatic β-cell will lead to a better understanding of how β-cell fate is controlled and maintained, as well as which genes are essential for postnatal function.


D. Scoville: None.

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