transcriptional regulation in islet cells

The pancreas is situated under the stomach and beside a section of the small intestine called the duodenum. The pancreas has two roles that are important for the processing of ingested nutrients. First, it synthesizes and secretes enzymes in a bicarbonate rich juice through a complex ductal structure into the duodenum. Here these enzymes are activated and carry out their essential job of breaking food down into readily absorbable units. Secondly, and of greater interest to us, the pancreas synthesizes and secretes endocrine hormones into the blood. The cells that produce these hormones are situated in tiny islands or groups of cells called islets of Langerhans, which are interspersed amongst the exocrine tissue. The most well known pancreatic hormone is insulin; it is produced in the pancreatic β-cell and is secreted in response to the elevated blood glucose levels that accompany eating. Insulin travels in the bloodstream to the target tissues where it regulates removal of glucose from the blood: thereby normalizing glucose levels. There are no other hormones that have a similar role to insulin in humans and loss of insulin effectiveness results in a disease known as diabetes mellitus.

The classical model of gene regulation relies upon sequence-specific interactions of nuclear proteins, called transcription factors, with the promoter regions of genes. The gene regulatory outcome of transcription factor binding to DNA is dependent on both the intrinsic properties of the factor and the regulatory or promoter context. Transcription factors have an indispensable role during all the stages of β-cell differentiation and in the adult β-cell. Our work has focused on a number of transcription factors important for β-cells; the specific questions we asked in this research were:

1) What role do Sox factors play during pancreas development?

We have demonstrated that Sox9 and Sox4 are important during β-cell development for proper development of endocrine progenitors. Recent studies suggest that Sox4 also regulates the cell cycle of adult β-cells. Current work seeks to understand how SOX4 increases the risk of developing Type 2 diabetes

2) What role does Npas4 play in adult β-cells?

We have demonstrated that Npas4 is activated when β-cells start to secrete insulin. Its role is to prevent excess β-cell cell stress and we hypothesize that it is important for maintaining β-cell function in those with diabetes. Current work is exploring the role of Npas4 in regulating feeding behaviour.

3) What role does the Mediator co-activator co-play in β-cells?

We have demonstrated that Mediator complex proteins are indispensible for β-cell development and remain important in the adult β-cell. Ongoing studies with the Taubert Lab are aimed at elucidating the mechanisms through which the Mediator complex prevents diabetes and how it regulates the function of glucagon-producing alpha cells