Epigenetic Studies of Diabetes

Diabetes mellitus is growing at an alarming rate globally. My dissertation aims at understanding the epigenetic mechanisms of Diabetes pathogenesis and how we can utilize this knowledge to develop treatments for patients with this debilitating disease.Diabetes is associated with loss of pancreatic beta cells and islet replacement therapy is limited by the source of donor islets. Two promising alternative approaches for beta cell replenishment are regeneration of endogenous beta cells and directed stem cell differentiation. In chapter 1, I used a transgenic mouse model that ectopically expresses Ezh2, to offset the loss of endogenous protein and uncovered new insights into plasticity of beta cell regeneration in adulthood. I show that reprogramming of the Ink4a chromatin by modulating the conserved Polycomb-Trithorax mechanism can rejuvenate the replication capacity of aged beta cells to provide a new strategy for beta cell expansion. In chapter 2, I studied mouse embryonic stem (ES) cells to understand endodermal lineage specification, as current attempts to bring endoderm-derived stem cell therapy to a state of effectiveness have been hampered by the paucity of knowledge of the underlying mechanisms. I show that the pluripotency transcription factors and epigenetic modifications of the chromatin interact in order to implement control pathways that drive differentiation of stem cells towards the definitive endoderm lineage.Type 1 Diabetes is caused by autoimmune assault of pathogenic T cells escaping the tolerance selection. In Chapter 3, I identified a novel interaction partner of the autoimmune regulator (Aire), JmjD6. My data suggest that JmjD6-mediated histone demethylation at Arginine 2 residues of target chromatin is essential to prime the chromatin of otherwise repressed peripheral tissue antigen (PTA), for subsequent Aire activation of the antigen peptides for tolerance selection.Maternal obesity is concerning because of the deleterious effects in offspring of increased risks of metabolic syndromes including Type 2 diabetes and obesity. My current work is focused on whole genome methylation mapping of trans-generational epigenetic inheritance in a maternal high-fat diet mouse model. The single nucleotide resolution of this screening will reveal information on how inherited methylation markers contribute to the predisposition of metabolic diseases in progeny in the context of maternal obesity, which can be further utilized for intervention and disease prevention