Altered AP-1, RUNX and EGR Chromatin Dynamics Drive Fibrotic Lung Disease

Overview

Journal bioRxiv

Date 2024 Nov 18

PMID 39554071

Authors

Eleanor Valenzi

Minxue Jia

Peter Gerges

Jingyu Fan

Tracy Tabib

Rithika Behara

Yuechen Zhou

John Sembrat

Jishnu Das

Panayiotis V Benos

Harinder Singh

Robert Lafyatis

Affiliations

Soon will be listed here.

Abstract

Pulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1 macrophages as drivers of fibrosis. Single-cell RNA sequencing has delineated fibroblast and macrophages transcriptomes, but limited insight into transcriptional control of profibrotic gene programs. To address this challenge, we analyzed multiomic snATAC/snRNA-seq on explanted SSc-ILD and donor control lungs. The neural network tool ChromBPNet inferred increased TF binding at single base pair resolution to profibrotic genes, including CTHRC1 and ADAM12, in fibroblasts and SPP1 and CCL18 in macrophages. The novel algorithm HALO confirmed AP-1, RUNX, and EGR TF activity controlling profibrotic gene programs and established TF-regulatory element-gene networks. This TF action atlas provides comprehensive insights into the transcriptional regulation of fibroblasts and macrophages in healthy and fibrotic human lungs.

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