EPIGENETIC REGULATIONS IN SJOGERN'S SYNDROME

Saliva performs a number of extremely important biological functions that are instrumental in maintaining oralhealth. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction(Sjogren's syndrome). Although no genes mutations have been identified that could explain the pathogenesisof Sjogren's syndrome (SS), recent evidence have suggested that T17-cell infiltration and induction ofapoptosis in salivary gland acinar cells could be the two major events that could lead to salivary glanddestruction. However, the molecular mechanism involved in the activation of T cells and apoptosis of salivaryacinar cells is not known. Interestingly, similar to other autoimmune diseases, females have been shown to beaffected with SS more than their male counterparts, with greater than 90% of SS cases being diagnosed inwomen. One hypothesis to explain this gender difference is that loss of random X-chromosome inactivationcould be the cause of this disease (since many genes involved in immune function are expressed on the X-chromosome); however, the reason for the loss of X-chromosome inactivation is not known in anyautoimmune disease, including SS. Results obtained from our ongoing studies indicate that a series of keyepigenetic changes are observed in SS patients. As a result transcription of a set of genes that are essentialfor controlling proper immune response may be decreased. In addition, loss of expression of XIST1 (that iscritical for random X-chromosome inactivation) may lead to the activation of certain genes on the X-chromosome that increases T cell activation, and initiates apoptosis. Furthermore, most of the loss ofmethylation on the X-chromosome was found in the CpG islands, which could lead to chromosomal instabilityand loss of imprinting. To further understand the mechanism, we performed a global RNA seq analysis oncontrol and SS samples and have identified that a master regulator gene ELF4 that is present on the X-chromosome was upregulated (due to loss of X-chromosome inactivation) and could assist in the pathology ofSS. These results are novel, and suggest a strong epigenetic origin for SS, but they need to be furthervalidated. Therefore, in this grant proposal we intend to thoroughly characterize the role of epigeneticchanges in salivary gland destruction and to determine the relationship between abnormal methylation and X-chromosome inactivation. The hypothesis of this study is that epigenetic changes along with the loss of X-chromosome inactivation alters ELF4 that increases susceptibility to immune changes and promote apoptosisof acinar cells, thereby leading to salivary gland destruction. Thus, identification of the mechanism as well asthe pathways that lead to salivary gland destruction could represent as drug targets in salivary glanddysfunction. We will coordinate our efforts in order to determine the functional significance of inhibitingepigenetic changes in order to protect against salivary gland destruction. The results of our studies areexpected to provide new insights into the role of epigenetic changes and the molecular mechanism involved insalivary gland destruction. Greater understanding of these events will be important in elucidating new therapyfor salivary gland dysfunctions and Sjgerns patients.