# Elucidating the Role of Dynamic X-Chromosome Inactivation Maintenance in the Pathogenesis of Systemic Sclerosis

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $214,500

## Abstract

Project Summary/Abstract:
Systemic sclerosis (SSc) is a systemic autoimmune disease that predominantly affects women and is associated
with significant morbidity and mortality due to fibrosis of the skin and internal organs. The molecular origin of this
striking female bias and its relationship to core aspects of the pathogenesis of SSc, including immune dysregu-
lation, multiorgan fibrosis, and vasculopathy, remains unclear. While there are known genetic risk variants asso-
ciated with SSc, the low monozygotic twin concordance rate has prompted investigation into the role of epige-
netic dysregulation in its pathogenesis. Importantly, the X-chromosome contains several proinflammatory and
profibrotic genes, and their appropriate expression in females is epigenetically regulated in part through X-chro-
mosome inactivation (XCI), a female-specific epigenetic mechanism that silences one of the two X chromosomes
in order to equalize X-linked gene dosage between XX females and XY males. XCI is maintained in somatic cells
by a variety of epigenetic modifications that are enriched on the inactive X chromosome (Xi), including the long
noncoding RNA XIST and additional heterochromatic histone modifications. We recently discovered that XCI
maintenance in T-cells from both humans and mice is “dynamic.” In “dynamic XCI maintenance”, XIST RNA and
heterochromatic marks are cytologically absent from the Xi in resting T-cells and subsequently relocalize to the
Xi upon in vitro cellular activation. We have found that dynamic XCI maintenance is impaired in T-cells from
women with lupus, another female-biased autoimmune disease, and is associated with aberrant X-linked gene
expression from the Xi. Based on the well-established role of T-cells in SSc-mediated pathology, the number of
X-linked proinflammatory and profibrotic genes, the aberrantly increased expression of many of these genes in
SSc T-cells, and our preliminary data, we hypothesize that impaired dynamic XCI maintenance in T-cells is a
pathogenic mechanism in SSc that accordingly contributes to the observed female bias. In Aim 1, we will use
single cell imaging to determine whether XCI maintenance is impaired in T-cells from females with SSc. We will
couple these analyses with transcriptomic studies to determine the contribution of the Xi to the observed X-linked
gene expression profile. In Aim 2, we will induce scleroderma-like disease in a novel mouse model of impaired
XCI maintenance to determine how impaired XCI maintenance in T-cells impacts T-cell-specific transcriptional
programs conferring susceptibility to fibrosis in SSc-relevant organs. Collectively, this work has the potential to
identify a novel epigenetic mechanism of female bias in SSc and will simultaneously identify which X-linked
genes become aberrantly expressed in T-cells during the development of fibrotic disease. These findings will
improve our understanding of how biological sex contributes to the pathogenesis of SSc and related fe...

## Key facts

- **NIH application ID:** 10511513
- **Project number:** 1R21AR081588-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Montserrat C Anguera
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $214,500
- **Award type:** 1
- **Project period:** 2022-09-12 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10511513

## Citation

> US National Institutes of Health, RePORTER application 10511513, Elucidating the Role of Dynamic X-Chromosome Inactivation Maintenance in the Pathogenesis of Systemic Sclerosis (1R21AR081588-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10511513. Licensed CC0.

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