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Publications of the Week

SOX4 Allows Facultative β-Cell Proliferation Through Repression of Cdkn1a

By May 31, 2017No Comments

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 This week we profile a recent publication in Diabetes from Dr. Francis Lynn (left) and Eric Xu (right)
at the BC Children’s Hospital Research Institute.

Can you provide a brief overview of your current research focus?

The Lynn Lab focuses on understanding the development, function and aging of insulin-producing pancreatic ß-cells with the goal of using our knowledge to be able to regenerate the functional ß-cell mass that is lost in those with diabetes. We use both human and mouse models to study ß-cells and are particularly interested understanding how transcription factors alter ß-cell function in health and disease.

What is the significance of the findings in this publication?

Genome-wide association studies have identified changes in numerous genomic regions that increase the risk for type 2 diabetes. One of these genomic locations was originally identified as a regulator of the gene Cdkal1, but was later re-attributed as a regulator of the DNA-binding transcription factor Sox4. This is the first paper to assess the impact of Sox4 knockout in the adult mouse pancreas. We demonstrated that loss of Sox4 predisposed the mice to diabetes by reducing ß-cell mass. We attributed this reduction in ß-cell mass to a decrease in ß-cell growth driven by increased expression of the cell-cycle inhibitor Cdkn1a(p21). Altogether, this study establishes how mutations in Sox4 regulatory regions might increase the risk for type 2 diabetes and demonstrates that Sox4, or its targets, might offer new ways to protect or regenerate ß-cell mass in those with diabetes.

What are the next steps for this research?

During the course of these studies RNAseq analyses on Sox4 knockout islets uncovered two new targets, in addition to p21, by which we believe Sox4 regulates ß-cell growth. We are now studying these factors by generating knockout mice, knockout hESC lines and by using clinically approved small molecules inhibitors.

This project was supported by:

Michael Smith Foundation for Health Research
BC Children’s Hospital Research Institute
Canucks for Kids Fund

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