Transcriptomic and Epigenetic Profiling of Fibroblasts in Idiopathic Pulmonary Fibrosis

Area of Science:

• Pulmonary Medicine
• Genomics
• Epigenetics

Background:

• Idiopathic pulmonary fibrosis (IPF) is a severe lung disease characterized by fibroblast expansion and excessive extracellular matrix deposition.
• Fibroblasts play a critical role in IPF development and progression, but the underlying genetic drivers are not fully understood.

Purpose of the Study:

• To investigate the hypothesis that differential chromatin accessibility contributes to genetic variations in IPF fibroblasts compared to healthy fibroblasts.
• To identify specific genes and pathways affected by these epigenetic changes in IPF.

Main Methods:

• Assay of transposase-accessible chromatin sequencing (ATAC-seq) was used to map genome-wide chromatin accessibility in IPF and healthy lung fibroblasts.
• RNA sequencing and single nucleotide polymorphism (SNP) analysis were performed to identify differentially expressed genes and IPF risk SNPs.
• Validation studies were conducted on isolated lung tissue.

Main Results:

• ATAC-seq identified distinct differentially accessible chromatin regions in IPF fibroblasts, enriched for transcription factor binding motifs like TWIST1 and FOXA1.
• RNA sequencing linked 93 genes to these regions, highlighting roles in cellular adhesion, cytoskeletal anchoring, and cell differentiation.
• Analysis revealed associations between IPF risk SNPs and accessible regions in key IPF-related genes (MUC5B, TERT, TOLLIP).
• Validation confirmed increased TWIST1 and FOXA1 expression and identified SHANK2 and CSPR2 as novel targets.

Conclusions:

• Differential chromatin accessibility is a significant mechanism in IPF pathogenesis.
• Epigenetic modifications influencing gene expression in fibroblasts are crucial for lung fibrosis development.
• Targeting these epigenetic changes offers potential therapeutic strategies for IPF.