ArticleGastroenterology2021
Epigenomic Evaluation of Cholangiocyte Transforming Growth Factor-β Signaling Identifies a Selective Role for Histone 3 Lysine 9 Acetylation in Biliary Fibrosis.
Article in Gastroenterology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
31 citing papers in PubMed, 50 citations in OpenAlex.
- Melatonin Alleviates Graft Biliary Fibrosis by Inhibiting VIMAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Lactylation in pulmonary fibrosis: current understanding and challenges.Journal of translational medicine · 2026Review
- GCN5 drives MASLD progression through LXRα/SREBP1c signaling pathway-mediated de novo lipogenesis.Nature communications · 2026Article
- Post-Translational Modifications of Histones and Non-Histones in Liver Disease and Traditional Chinese Medicine Treatment: A Narrative Review.Pharmacogenomics and personalized medicine · 2026Review
- Senkyunolide A interrupts TRAF6-HDAC3 interaction to epigenetically suppress c-MYC and attenuate cholestatic liver injury.Journal of advanced research · 2026Article
- Transforming growth factor-β1 triggers the proliferation of human cholangiocyte spheroids via interleukin-6-mediated STAT3 signaling.Molecular biology reports · 2025Article
- Central role for cholangiocyte pathobiology in cholestatic liver diseases.Hepatology (Baltimore, Md.) · 2025Review
- Aramchol attenuates fibrosis in mouse models of biliary fibrosis and blocks the TGFβ-induced fibroinflammatory mediators in cholangiocytes.Hepatology communications · 2025Article
- Review
- Microenvironmental control of the ductular reaction: balancing repair and disease progression.Cell death & disease · 2025Review
- Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies.Cell death discovery · 2025Review
- Alleviation of liver fibrosis by inhibiting a non-canonical ATF4-regulated enhancer program in hepatic stellate cells.Nature communications · 2025Article
- Multi-omics perspective: mechanisms of gastrointestinal injury repair.Burns & trauma · 2025Review
- Dynamic crosstalk between HSCs and liver microenvironment: multicellular interactions in the regulation of liver fibrosis.Frontiers in cell and developmental biology · 2025Review
- Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application.Signal transduction and targeted therapy · 2024Review
- Noncoding RNA-Mediated Epigenetic Regulation in Hepatic Stellate Cells of Liver Fibrosis.Non-coding RNA · 2024Review
- Histone 3 lysine 9 acetylation-specific reprogramming regulates esophageal squamous cell carcinoma progression and metastasis.Cancer gene therapy · 2024Article
- Epigenetic modification in liver fibrosis: Promising therapeutic direction with significant challenges ahead.Acta pharmaceutica Sinica. B · 2024Review
- Unraveling the complexities of fibrosis and ductular reaction in liver disease: pathogenesis, mechanisms, and therapeutic insights.American journal of physiology. Cell physiology · 2024Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsTransforming growth factor β (TGFβ) upregulates cholangiocyte-derived signals that activate myofibroblasts and promote fibrosis. Using epigenomic and transcriptomic approaches, we sought to distinguish the epigenetic activation mechanisms downstream of TGFβ that mediate transcription of fibrogenic signals.
methodsChromatin immunoprecipitation (ChIP)-seq and RNA-seq were performed to assess histone modifications and transcriptional changes following TGFβ stimulation. Histone modifications and acetyltransferase occupancy were confirmed using ChIP assays. Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) was used to investigate changes in chromatin accessibility. Cholangiocyte cell lines and primary cholangiocytes were used for in vitro studies. Mdr2
resultsTGFβ stimulation caused widespread changes in histone 3 lysine 27 acetylation (H3K27ac), and was associated with global TGFβ-mediated transcription. In contrast, H3K9ac was gained in a smaller group of chromatin sites and was associated with fibrosis pathways. These pathways included overexpression of hepatic stellate cell (HSC) activators such as fibronectin 1 (FN1) and SERPINE1. The promoters of these genes showed H3K9ac enrichment following TGFβ. Of the acetyltransferases responsible for H3K9ac, cholangiocytes predominantly express Lysine Acetyltransferases 2A (KAT2A). Small interfering RNA knockdown of KAT2A or H3K9ac inhibition prevented the TGFβ-mediated increase in FN1 and SERPINE1. SMAD3 ChIP-seq and ATAC-seq suggested that TGFβ-mediated H3K9ac occurs through SMAD signaling, which was confirmed using colocalization and genetic knockdown studies. Pharmacologic inhibition or cholangiocyte-selective deletion of Kat2a was protective in mouse models of biliary fibrosis.
conclusionsCholangiocyte expression of HSC-activating signals occurs through SMAD-dependent, KAT2A-mediated, H3K9ac, and can be targeted to prevent biliary fibrosis.
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