# Epigenetic gene repression in pulmonary fibrosis

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $412,500

## Abstract

PROJECT SUMMARY
Pulmonary fibrosis represents an increasing cause of mortality worldwide and despite decades of investigation,
considerable uncertainty exists as how this disease initiates and progresses. While multiple fibrogenic
molecules have been found to drive aberrant matrix deposition, the mechanisms responsible for maintaining
persistent and self-sustaining fibrogenesis are largely unknown. Targeting mechanisms that perpetuate the
pathological state of fibroblasts during disease progression may serve as an attractive therapeutic strategy to
halt lung fibrosis. The current proposal addresses the role of epigenetic gene repression in regulating fibroblast
activation and lung fibrosis development. We will investigate the role of histone 3 lysine 9 methylation
(H3K9me) as an important epigenetic modification that represses the transcription of genes essential to
maintaining or returning lung fibroblasts to an anti-fibrotic or quiescent inactive state. Our preliminary data
demonstrate that inhibition of H3K9 methylation by targeting the H3K9 methyltransferase G9a or the epigenetic
reader CBX5 potently inhibits fibroblast activation by fibrogenic stimuli. Mechanistically, our data demonstrate
that both G9a and CBX5 are directly involved in repressing PGC1, a master regulator of mitochondria
metabolism significantly downregulated in diseased lung fibroblasts. Loss of PGC1 expression promotes
fibroblast activation, while restoring PGC1 via epigenetic mechanisms reverses fibroblast activation. We will
use loss of function strategies to target the epigenetic regulators CBX5 and G9a to investigate their
mechanistic roles in switching fibroblasts between activated and quiescence states. Using mouse genetics
approaches we will investigate the benefits of inhibiting H3K9 methylation in halting disease progression in
bleomycin-induced lung fibrosis models. As our preliminary data strongly support an anti-fibrotic function for
PGC1 during lung fibroblast activation in vitro, in this proposal we will further characterize its anti-fibrotic
function and evaluate upstream and downstream transcriptional network that mediate its anti-fibrotic functions.
Taken together, the proposed research studies will reveal critical epigenetic targets for therapeutic
interventions aimed at halting or reversing the progression of pulmonary fibrosis.

## Key facts

- **NIH application ID:** 10197207
- **Project number:** 5R01HL142596-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Giovanni Ligresti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,500
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197207

## Citation

> US National Institutes of Health, RePORTER application 10197207, Epigenetic gene repression in pulmonary fibrosis (5R01HL142596-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197207. Licensed CC0.

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