Transcription factor ATF3 aggravates kidney fibrosis by maintaining the state of histone H3 lysine 27 acetylation.

Abstract

Background: Chronic kidney disease (CKD) is a global health issue, with renal fibrosis being a common pathway in CKD development. Histone modification plays crucial roles in transcriptional regulation, but their pathological functions and mechanisms in CKD are not well understood.

Methods: We utilized chromatin immunoprecipitation with next-generation DNA sequencing (ChIP-seq) and RNA-seq to evaluate the states and functions of H3 lysine 27 acetylation (H3K27ac) and H3 lysine 4 trimethylation (H3K4me3) in kidney of CKD mice. We identified epigenetic factors regulating H3K27ac through motif analysis. Expression of activating transcription factor 3 (ATF3) in CKD mouse models and patients' kidneys was validated via immunofluorescence staining or Western blot. We further generated the Atf3 deficient (Atf3-/-) mice to explore its effect in kidney function and fibrosis. ChIP-seq of H3K27ac from Atf3-/- CKD mice was employed to validate ATF3's regulatory effects. We explored how ATF3 maintains the state of H3K27ac by integrating the data sources from multiple databases.

Results: The states of H3K27ac and H3K4me3 were changed during CKD, and positively correlated with differential gene expression. ATF3 was highly expressed in kidney of both patients and mice with CKD, and co-localized with H3K27ac in genome, epigenetically regulating H3K27ac state. Atf3 deficient in CKD mice significantly ameliorated kidney dysfunction and fibrotic phenotype, and reduced H3K27ac levels at the ATF3 binding sites. Mechanically, ATF3 may recruit the histone acetyltransferases (HATs) network to maintain the H3K27ac state during CKD.

Conclusion: ATF3 promotes kidney injury and fibrosis in CKD by maintaining the state of H3k27ac via recruiting HATs network.