# Epigenetic Regulation of the Maturation and Function of Lung Epithelium by the SWI/SNF Proteins ARID1A and ARID1B.

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $357,750

## Abstract

PROJECT SUMMARY:
 It is being increasingly recognized that changes in chromatin state are associated with a wide spectrum of
lung diseases, ranging from bronchopulmonary dysplasia (BPD) to chronic obstructive pulmonary disease
(COPD). However, the mechanisms by which these changes contribute to the pathogenesis of these diseases,
and how to manipulate the epigenome for therapeutic benefit, remains largely unknown. Modulation of chromatin
accessibility is an important epigenetic mechanism by which gene expression is controlled, even across repeated
cell divisions. However, as a prerequisite to understanding how altered chromatin accessibility contributes to
disease, the mechanisms by which chromatin accessibility patterns first establish and maintain cellular identity
within the lung must be defined.
 This proposal is based on studies from our group that identified the SWI/SNF proteins Arid1a and Arid1b
as key mediators of the chromatin accessibility changes that occur during development of the SOX9+ lung
epithelial stem/progenitor cell population. Our data demonstrate that loss of Arid1a or Arid1b led to persistence of
the SOX9+ progenitor cell population, impaired alveolar differentiation, and neonatal death due to respiratory
distress. In addition, ARID1A directly interacts with NKX2-1 and SOX9. The central hypothesis of the present
proposal is that ARID1A and ARID1B interact with key lung developmental TFs to direct the SWI/SNF complex to
remodel chromatin at specific loci, silencing progenitor cell gene expression programs and promoting the
maturation and function of the mature alveolar epithelium. The proposed studies will: A) Define the role that
Arid1a/Arid1b, and the larger SWI/SNF complex, play in establishment of mature alveolar cell type identify in
mouse and human. B) Identify the mechanism(s) by which the SWI/SNF complex remodels chromatin, in
conjunction with key lung transcription factors, to establish and maintain gene expression modules controlling
type I & II AEC identity and function. C) Determine how Arid1a/Arid1b-mediated chromatin remodeling contributes
to the lung epithelial repair response following influenza infection.
 These studies will provide conceptual advances in our understanding of how mature alveolar epithelial
cells are established and maintained, how the chromatin accessibility landscape interacts with previously well-
defined transcription factor networks, and how chromatin remodeling directs the normal repair process after lung
injury. Emerging epigenomic tools and systems biology approaches will be applied to the epithelium for the first
time. Taken together, these data will inform future translational studies seeking to understand how alterations in
the epigenome contribute to lung disease, and will provide a foundation for future efforts to manipulate the lung’s
epigenomic code to restore normal lung structure and function.

## Key facts

- **NIH application ID:** 10831429
- **Project number:** 5R01HL156860-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Debora Sinner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $357,750
- **Award type:** 5
- **Project period:** 2021-05-20 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831429

## Citation

> US National Institutes of Health, RePORTER application 10831429, Epigenetic Regulation of the Maturation and Function of Lung Epithelium by the SWI/SNF Proteins ARID1A and ARID1B. (5R01HL156860-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10831429. Licensed CC0.

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