STAT3 Facilitates Super Enhancer Formation to Promote Fibroblast-To-Myofibroblast Differentiation by the Analysis of ATAC-Seq, RNA-Seq and ChIP-Seq

Abstract

A cellular characteristic of IPF is the transformation of fibrosis into myofibroblasts. This study identifies several transcription factors—STAT3, FOXP1, JUNB, ATF3, FosL2, BATF, Fra2 and AP-1—that play crucial roles in promoting pulmonary fibrogenesis. They achieve this by facilitating the differentiation of fibroblasts into myofibroblasts, as analysed through ATAC-seq and RNA-seq. Additionally, STAT3 ChIP-seq showed that STAT3 is significantly concentrated in accessible chromatin regions, including introns and intergenic areas. H3K27ac ChIP-seq and Co-IP demonstrated that STAT3 plays a role in the formation of super enhancer (SE), which promotes gene expression. CUT&RUN-qPCR and the pGL3-SE dual-luciferase reporter system assays proved that STAT3 enhanced pGL3-SE activities by facilitating H3K27ac modification, leading to promoting the transcription of target genes including RUNX1, JUNB, JUN, SMAD6, COL3A1 and PTPN1. In summary, this study shows that STAT3 contributes to the formation of SEs that accelerate the differentiation of fibroblasts into myofibroblasts, leading to IPF. This insight enhances our understanding of STAT3-related SEs and offers potential therapeutic strategies for fibrotic diseases.