Transposable element silencing as a regulator of salivary gland immune homeostasis

/ABSTRACT Sjogren’s syndrome (SjS) is a chronic autoimmune disorder marked by salivary and lacrimal gland dysfunction, lymphocytic infiltration, and progressive secretory decline. While traditionally viewed as immune cell–driven, emerging evidence suggests that epithelial cells may initiate local inflammation. However, the molecular triggers originating from epithelial cells remain poorly defined. Transposable elements (TEs), including endogenous retroviruses (ERVs) and LINEs, are normally repressed through DNA methylation, histone modifications, and heterochromatin organization. Failure of TE silencing mechanisms due to aging, hormonal changes, or stress results in cytoplasmic dsRNA accumulation, nucleic acid sensor activation, and type I interferon signaling. These TE-derived nucleic acids are increasingly recognized as endogenous triggers of immunological stress that disrupt cellular homeostasis. Our preliminary data show widespread TE derepression and upregulation of interferon-stimulated genes in salivary glands from patients with SjS. To mimic this phenomenon, we will inducibly delete Setdb1, a key histone H3K9 methyltransferase, in defined epithelial compartments of the salivary gland. This will allow us to model compartment-specific TE derepression and assess its impact on both innate immune activation and adaptive immune responses. We will also test how aging and estrogen deficiency disrupt TE repression in basal/ductal versus acinar cells using lineage tracing and epigenomic profiling. Finally, we will evaluate the therapeutic potential of reverse transcriptase inhibitors and chromatin-modifying drugs in attenuating TE-driven inflammation. This exploratory study will uncover how failure of TE silencing contributes to epithelial-driven autoimmunity in SjS and will provide a foundation for future targeted epigenetic manipulations in human tissues and patients. Project Number: 1R21DE036015-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Andrey Sharov | Institution: BOSTON UNIVERSITY MEDICAL CAMPUS, BOSTON, MA | Award Amount: $449,625 | Activity Code: R21 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11356485