Transcriptomic and Epigenetic Profiling of Fibroblasts in Idiopathic Pulmonary Fibrosis

Ankit Hanmandlu, Lisha Zhu, Tinne C.J. Mertens, Scott Collum, Weizhen Bi, Feng Xiong, Ruoyu Wang, Rajarajan T. Amirthalingam, Dewei Ren, Leng Han, Soma S.S.K. Jyothula, Wenbo Li, W. Jim Zheng, Harry Karmouty-Quintana

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Idiopathic pulmonary fibrosis (IPF), a devastating, fibroproliferative, chronic lung disorder, is associated with expansion of fibroblasts/myofibroblasts, which leads to excessive production and deposition of extracellular matrix. IPF is typically clinically identified as end-stage lung disease, after fibrotic processes are well-established and advanced. Fibroblasts have been shown to be critically important in the development and progression of IPF. We hypothesize that differential chromatin access can drive genetic differences in IPF fibroblasts relative to healthy fibroblasts. To this end, we performed assay of transposase-accessible chromatin sequencing to identify differentially accessible regions within the genomes of fibroblasts from healthy and IPF lungs. Multiple motifs were identified to be enriched in IPF fibroblasts compared with healthy fibroblasts, including binding motifs for TWIST1 and FOXA1. RNA sequencing identified 93 genes that could be annotated to differentially accessible regions. Pathway analysis of the annotated genes identified cellular adhesion, cytoskeletal anchoring, and cell differentiation as important biological processes. In addition, single nucleotide polymorphism analysis showed that linkage disequilibrium blocks of IPF risk single nucleotide polymorphisms with IPF-accessible regions that have been identified to be located in genes that are important in IPF, including MUC5B, TERT, and TOLLIP. Validation studies in isolated lung tissue confirmed increased expression for TWIST1 and FOXA1 in addition to revealing SHANK2 and CSPR2 as novel targets. Thus, modulation of differential chromatin access may be an important mechanism in the pathogenesis of lung fibrosis.

Original languageEnglish (US)
Pages (from-to)53-63
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume66
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • ATAC sequencing
  • Epigenetics
  • Fibroblasts
  • Idiopathic pulmonary fibrosis
  • RNA sequencing

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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