Role of m6A methylation of RNA in salivary gland epithelial cells in Sjögren’s syndrome – METRESS

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease associated with damage to multiple organs including the salivary and lachrymal glands, as a consequence of abnormal B and T cell responses. Activation of salivary gland epithelial cells (SGEC) drives the pathogenesis of pSS by up-regulating interferon
signaling pathway and genes involved in immune responses. Therefore, unlike normal protective immunity where inflammation is terminated after the infection is cleared, pSS is sustained by chronic inflammation of the exocrine glands. In particular, the signaling of pro-inflammatory immune triggers has been implicated in SGEC damage during pSS. Understanding the signaling pathways and mechanisms that promote SGEC dysfunction will ultimately provide potential therapeutic targets for pSS. Often, induction of inflammatory genes is viewed in the context of promoter regulation, but several immune genes are expressed at baseline tonic levels, and their ability to be induced is mediated by post transcriptional control of mRNA. Notably, RNA methylation of adenosine at
the 6th nitrogen position (aka, N6-methyladenosine; m6A) is dynamically regulated by several methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). Specifically, the writers catalyze the m6A
addition while erasers reverse this modification. The readers bind to m6A-modified RNA and impact RNA expression. Recently, several immune mRNAs were shown to carry m6A marks. However, the immunological ramifications of m6A modifications have been largely overlooked, and to date nothing is known regarding the role of m6A machinery in pSS. The overall goal of this application is to define the mechanisms by which this novel epitrancriptomic RNA regulation controls immune trigger-dependent signal transduction in SGEC, with the long term objective of using this fundamental knowledge to develop therapies that involve this pathway.