Estrogen-mediated disruption of an E-cadherin - associated RNAi machinery promotes fibrotic diseases in women

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PROJECT SUMMARY Fibrotic and inflammatory conditions with severe clinical manifestations in the gastrointestinal tract, such as Scleroderma (SSc) and Crohn’s Disease (CD), are significantly more prevalent in women, posing substantial challenges to their health and well-being. However, the mechanisms explaining the higher incidence and severity of these diseases in women are still not well-understood. Compromised epithelial integrity is a common feature of these conditions. We have discovered a mechanism that links epithelial tissue integrity with the RNA interference (RNAi) machinery, miRNA regulation, and colon epithelial cell behavior. We have shown that the adherens junctions, which is an essential architectural component of the cell, recruit the microprocessor and the RNAi-induced silencing complex (RISC), the core components of the RNAi machinery, as well as a specific set of miRNAs and mRNAs, in colon epithelial cells. This interaction occurs through PLEKHA7, a member of the E- cadherin cell-cell adhesion complex. PLEKHA7 loss results in compromised epithelial integrity, decreased levels and silencing activity of a set of miRNAs, increased mRNA expression of growth promoters and epithelial cell transformation. We have also found extensive dysregulation of PLEKHA7 and of the junctional RNAi machinery in colon cancer. Our preliminary data show that disruption of the junctional RNAi results in overexpression of extracellular matrix (ECM) and pro-inflammatory regulators and promotes ECM remodeling. It has been demonstrated that estrogens may disrupt adherens junction integrity through Src activation. We have reported that activated Src indeed opposes RNAi recruitment to the junctions. Based on these findings, we hypothesize that estrogen – Src mediated disruption of the epithelial adherens junction-associated RNAi machinery and miRNA dysregulation promotes ECM remodeling, inflammation, and fibrosis in women. We will examine our hypothesis under two specific Aims: 1) estrogens promote ECM remodeling through disruption of the adherens junction – associated RNAi machinery; 2) disruption of the adherens junction – associated RNAi machinery is more frequent in the female gut and correlates with higher SSc and CD incidence. This study is significant, since it may identify a molecular mechanism explaining the strong prevalence of fibrotic diseases in women, which is currently missing. The proposed work is innovative, by introducing the concept of localized RNAi regulation by estrogens at adherens junctions. The impact of the study is that it will advance our understanding of the underlying mechanistic causes of diseases that pose significant burden on women’s health, offering opportunities for therapeutic intervention. Since this involves miRNA regulation as the focal point of this mechanism, the study can lead to future development of RNA-based therapeutics. There will be no change in the parent grant resulting from this proposed supplement.