Discovering miR6891-5p: guardian of XX allelic balance and barrier to Sjögren’s syndrome pathogenesis

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ABSTRACT Primary Sjögren's syndrome (pSS), occurring in 1.4 million people in the United States, is the most female- predominant autoimmune disease with a female-to-male ratio of 14:1. While the sex chromosome has been proposed to impact the female bias in pSS, the exact molecular mechanism of X chromosome regulation in pSS- relevant tissues remains elusive. To close this knowledge gap, this project focuses on the regulatory mechanisms controlling the expression of escapees, genes that escape X-chromosome inactivation (XCI), in minor salivary gland-derived mesenchymal stromal cells (MSCs). The intriguing finding that escapees exhibit marked skewing in pSS but not control MSCs underscores the importance of maintaining allelic balance in preventing pSS pathogenesis. Therefore, the objective of this project is to elucidate the molecular checkpoints ensuring allelic balance of escapee expression. The project will test the central hypothesis that dysregulation of miR6891-5p, a HLA-encoded noncoding RNA, leads to skewed escape from XCI in Sjögren's syndrome: Aim 1. Elucidate the functional consequence of restoring miR6891-5p expression in reversing X skewing and inflammatory differentiation of pSS MSCs. Aim 2. Establish the molecular mechanism by which miR6891-5p regulates escape from XCI. Aim 3. Determine the genetic and epigenetic interplay of miR6891-5p-regulated XCI escape. This project will allow us to gain insights into the molecular underpinnings of pSS-associated X chromosomal abnormalities as well as their contribution to the female bias in pSS. By establishing miR6891-5p as a critical gatekeeper against X skewing, this work will provide a novel clinical target for the treatment of pSS and additional autoimmune diseases.