# Role of DNA methylation in lupus

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $488,112

## Abstract

Abstract
 Epigenetic dysregulation plays an important role in the pathogenesis of lupus. We
recently described a pro-inflammatory epigenetic reprogramming of naïve CD4+ T cells upon
increased disease activity in lupus patients. Our data suggest that the epigenetic regulator
EZH2 might be mediating these epigenetic changes. Indeed, we show that EZH2 is increased in
CD4+ T cells from lupus patients, and that both miR-26a and miR-101 which regulate EZH2 are
downregulated. Both microRNAs have been shown to be sensitive to glucose concentrations,
and we show that inhibiting glycolysis restores the expression of these two microRNAs in lupus
CD4+ T cells. We hypothesize that increased glycolysis in lupus CD4+ T cells, results in
upregulation of EZH2 via downregulating miR-26a and miR-101. Further, we provide evidence
that EZH2 overexpression in lupus CD4+ T cells upregulates JAM-A which mediates increased
T cell adhesion. We propose to determine a mechanistic explanation of EZH2 overexpression in
lupus CD4+ T cells and how this might be linked to increased glycolysis and mTORC1
signaling. We will also identify the complete repertoire of genes and pathways dysregulated by
EZH2 overexpression in lupus CD4+ T cells to identify novel therapeutic targets. In addition,
given our data suggesting abrogation of increased CD4+ T cells adhesion in lupus patients
following EZH2 inhibition in vitro, and that EZH2 inhibition in vivo significantly improves survival
and ameliorates lupus-like disease in MRL/lpr lupus-prone mice, we propose to use genetic
approaches to characterize the effects of targeted CD4+ T cell Ezh2 deletion in a murine model
of lupus. EZH2 inhibitors are currently being trialed for a number of malignancies, and therefore,
our results will pave the way for targeting EZH2, or EZH2-regulated genes we will identify, in
lupus patients.

## Key facts

- **NIH application ID:** 9969738
- **Project number:** 2R01AI097134-06A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Amr H Sawalha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $488,112
- **Award type:** 2
- **Project period:** 2013-02-25 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969738

## Citation

> US National Institutes of Health, RePORTER application 9969738, Role of DNA methylation in lupus (2R01AI097134-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9969738. Licensed CC0.

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