Novo Nordisk Fonden - Nutrient-induced reprogramming of gene expression and function of pancreatic beta-cells

Project: Research

Project Details

Description

Pancreatic beta-cells are highly sensitive to nutrients. Not only do nutrients acutely regulate insulin secretion, they also induce long-term adaptive changes in gene expression that leads to changes in proliferative potential and suppression of beta-cell specific genes and functions.

The overall aim of this project is to obtain detailed and comprehensive insight into the transcriptional networks involved in glucose- and fatty acid-induced reprogramming of gene expression in pancreatic beta-cells. We will use genome-wide technologies for unbiased global identification of regulatory regions involved in the control of gene expression by nutrients. Based on the sequence information in these regions, we will predict novel transcriptional mediators and subsequently use RNAi-mediated knockdown to study the potential role of candidate transcription factors in the regulation of beta-cell gene expression, proliferative potential and (dys)function. Genome-wide profiling of candidate factors and their co-factors will be used to delineate transcriptional networks affected by nutrients and define nutrient sensitive transcription factor hotspots in the genome. Using genomic footprinting we will determine the organization of factors in these hotspots. For selected factors we will investigate the detailed molecular mechanisms underlying the regulation by nutrients as well as their specific roles in the transcriptional networks of betacells.

We expect this project to identify several novel factors and regulatory nodes involved in regulation of gene expression by nutrients in pancreatic beta-cells. This will significantly enhance our understanding of the transcriptional mechanisms involved in beneficial nutrient-induced adaptive changes in pancreatic beta-cell as well as the adverse effects during glucolipotoxicity. These results are expected to contribute to the long term ambition of controlling beta-cell function and proliferation for the treatment of type 2 diabetes.
StatusFinished
Effective start/end date01/10/201230/09/2015