Disallowed pancreatic beta-cell genes.

The lab of the applicant recently published a large scale genome-wide mRNA expression study in the mouse in which some housekeeping genes were found to be tissue-specifically repressed (Thorrez et al, 2011). This novel phenomenon of disallowed genes is the mirror of tissue-specific expression and is achieved during maturion of the differentiated cell via chromatin methylation and microRNA-mRNA interactions. Three examples of disallowed genes in beta cells (MCT1, LDHA and HK1) underline the importance for the physiology of insulin release, avoiding the inappropriate release of insulin and the toxic consequences of hypoglycemia (Quintens et al, 2008). These examples suggests that other cases of relevant disallowed genes may exist. In this project we want to assess the importance of environmental factors on the state of disallowance. We plan to study the influence of age, diet and intra-uterine history on islet expression levels of disallowed genes. High fat diet will be tested against control diet as the former is often reported to trigger beta cell failure in models of type 2 diabetes. During pregnancy we want to address the idea that maternal serotonin influences the imprining program of islet disallowed genes. This project is the first to study the effect of environment on tissue-specific gene repression and we anticipate to learn new facts about what is a beta cell and how it regulates blood glucose.

Keywords:Serotonin, Pancreatic, Epigenetics, Pregnancy, MicroRNA, Gene expression, High fat diet, Disallowed genes

Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences