# Epigenetic regulations in Sjogern's syndrome

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $362,188

## Abstract

Project Summary
Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral
health. 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 pathogenesis
of Sjogren's syndrome (SS), recent evidence have suggested that T17-cell infiltration and induction of
apoptosis in salivary gland acinar cells could be the two major events that could lead to salivary gland
destruction. However, the molecular mechanism involved in the activation of T cells and apoptosis of salivary
acinar cells is not known. Interestingly, similar to other autoimmune diseases, females have been shown to be
affected with SS more than their male counterparts, with greater than 90% of SS cases being diagnosed in
women. One hypothesis to explain this gender difference is that loss of random X-chromosome inactivation
could 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 any
autoimmune disease, including SS. Results obtained from our ongoing studies indicate that a series of key
epigenetic changes are observed in SS patients. As a result transcription of a set of genes that are essential
for controlling proper immune response may be decreased. In addition, loss of expression of XIST1 (that is
critical 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 of
methylation on the X-chromosome was found in the CpG islands, which could lead to chromosomal instability
and loss of imprinting. To further understand the mechanism, we performed a global RNA seq analysis on
control 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 of
SS. These results are novel, and suggest a strong epigenetic origin for SS, but they need to be further
validated. Therefore, in this grant proposal we intend to thoroughly characterize the role of epigenetic
changes 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 apoptosis
of acinar cells, thereby leading to salivary gland destruction. Thus, identification of the mechanism as well as
the pathways that lead to salivary gland destruction could represent as drug targets in salivary gland
dysfunction. We will coordinate our efforts in order to determine the functional significance of inhibiting
epigenetic chan...

## Key facts

- **NIH application ID:** 9960306
- **Project number:** 5R01DE022765-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Brij B Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,188
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960306

## Citation

> US National Institutes of Health, RePORTER application 9960306, Epigenetic regulations in Sjogern's syndrome (5R01DE022765-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9960306. Licensed CC0.

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