Diabetes and other autoimmune endocrine diseases
The responses of tissues to autoimmune attack may play a role in the susceptibility and control of disease by controlling differentiation, survival mechanisms, or even cell death. The development of beta-cells is highly regulated by epigenetic mechanisms. However, there is little known about the epigenetic responses of beta-cells to the chronic inflammation leading to disease. Oxidative conversion of 5mC to 5-hydroxymethylcytosine (5hmC) by Ten Eleven Translocation (Tet) enzymes constitutes a key step towards active DNA demethylation.
We provide evidence that TET2 protein is a key component of diabetes pathogenesis. During progression of diabetes in NOD mice, there is increased expression of Tet2 in beta-cells that are infiltrated with immunocytes. NOD mice lacking Tet2 have normal glucose tolerance but beta-cells are resistant to killing when the mice receive transfer of diabetogenic splenocytes. In the pancreata from humans with autoimmune or chronic pancreatitis, TET2 expression is increased in beta-cells but is reduced overall in the exocrine tissue. Further work revealed that due to lack TET2, beta-cells are desensitized to inflammation and autoimmunity, potentially through reduced IL-6 receptors and thus are insensitive to a feedforward mechanism of killing by IL-6 that can be released by inflamed beta-cells and infiltrating immune cells.
Together, our data show the importance of TET2 pattern in maintaining the beta-cells homeostasis, and the epigenetic responses of the cells to immune attack. Our studies highlight the potential remodeling of beta-cell epigenetic landscape by TET2 protein as a key component of diabetes pathogenesis.