transcriptional control of β-cell genesis
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:
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.
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.
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 are aimed at elucidating the mechanisms through which the Mediator complex prevents diabetes.
Figure 1: Model illustrating the position of Sox9 and other transcription factors in the development from gut endoderm to the mature pancreatic cell types.