# Regulatory Role of Chromosome 11p13 in Cystic Fibrosis Lung Disease Severity

> **NIH NIH F31** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $6,670

## Abstract

PROJECT SUMMARY/ABSTRACT
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cannot fully explain lung
disease phenotype in cystic fibrosis (CF). Previous genome-wide association studies (GWAS) identified
additional regions of the genome correlating with CF lung disease severity. One of these sites lies within the
intergenic region between E47 like ETS transcription factor 5 (ELF5) and Ets-homologous factor (EHF), and
Apaf-1 interacting protein (APIP) at chromosome 11p13. ELF5 is known to have significant roles in breast cancer
and is thought to confer susceptibility to asthma in specific populations. EHF is a critical regulator of injury
response and inflammation in the lung, and APIP has an important role in apoptosis. Our goal was to determine
the functional significance of this region, which is predicted to be regulatory, since it lacks annotated genes. Cis-
regulatory elements within the 11p13 modifier region were first identified in lung epithelial cells by mapping open
chromatin using DNase I digestion and deep sequencing (DNase-seq). Next, histone modifications associated
with active chromatin, H3K4me1 and H3K27ac, were revealed by chromatin immunoprecipitation. Predicted
enhancer elements were assayed in bronchial epithelial cells using luciferase reporter genes. Two elements
showed strong enhancer activity for the promoters of both EHF and ELF5. No enhancers of the APIP promoter
were found. To determine direct physical interactions between cis-regulatory elements and gene promoters
within 11p13, we used circular chromosome conformation capture and deep sequencing (4C-seq). 4C-seq
confirmed the enhancer-promoter associations, identified additional interacting elements and defined CCCTC-
binding factor (CTCF)-enriched boundaries of the topologically associated domains (TADs) at 11p13. No strong
interactions were observed with the APIP promoter, which lies outside of the main TAD or sub-TAD
encompassing the GWAS signal. These results focus attention on the likely role of EHF and ELF5 in modifying
CF lung disease severity. We hypothesize that these epithelial selective genes are regulated by cis-elements
found at 11p13, and that the dysregulation of these genes contributes to CF lung disease severity. We aim to
test this hypothesis in two ways. First, we will use clustered regularly interspaced short palindromic repeats
(CRISPR)/Cas9 to remove or mutate cis-regulatory elements across the TAD in airway epithelial cells. Evaluation
of transcription factor binding, histone modifications, gene expression and chromatin landscape in the modified
cells will reveal key regulatory mechanisms at 11p13. Second, we will use VPR-mediated activation of promoters
and cis-elements across 11p13 in a human bronchial epithelial cell line. This will reveal the functional impact of
activating gene expression on key cellular processes such as migration, proliferation and apoptosis. In
conjunction with these experiments, we will use c...

## Key facts

- **NIH application ID:** 10147146
- **Project number:** 5F31HL146010-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Hannah Swahn
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $6,670
- **Award type:** 5
- **Project period:** 2019-05-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147146

## Citation

> US National Institutes of Health, RePORTER application 10147146, Regulatory Role of Chromosome 11p13 in Cystic Fibrosis Lung Disease Severity (5F31HL146010-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10147146. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*