The histone demethylase KDM4D promotes hepatic fibrogenesis by modulating Toll-like receptor 4 signaling pathway
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Abstract
BACKGROUND: Accumulating evidence has revealed the pivotal role of epigenetic regulation in the pathogenesis of liver disease. However, the epigenetic mechanism that accounts for hepatic stellate cells (HSCs) activation in liver fibrosis remains largely unknown. METHODS: Primary HSCs were used to screen the differentially expressed histone H3 lysine methyltransferases and demethylases during HSC activation. Loss-of-function experiments were applied to determine the cellular functions of KDM4D in HSCs. Transcriptome analysis was applied to explore the downstream targets of KDM4D. Real-time qPCR, western blotting, immunohistochemical staining, and chromatin immunoprecipitation were performed to uncover the underlying mechanism concerning KDM4D during liver fibrogenesis. FINDINGS: -induced mice model, Kdm4d knockdown inhibited fibrosis progression, and promoted fibrosis reversal, with enhanced thinning and splitting of fibrotic septa, as well as a dramatic decrease in collagen area. Whole gene transcriptome analysis showed the regulatory role of KDM4D in Toll-Like Receptor (TLR) signaling pathway. Mechanistically, KDM4D catalyzed histone 3 on lysine 9 (H3K9) di-, and tri-demethylation, which promoted TLR4 expression, and subsequently prompted liver fibrogenesis by activating NF-κB signaling pathways. INTERPRETATION: KDM4D facilitates TLR4 transcription through demethylation of H3K9, thus activating TLR4/NF-κB signaling pathways in HSCs, contributing to HSC activation and collagen crosslinking, further, hepatic fibrosis progression. FUND: Shanghai New Hundred Talents Program, Shanghai Municipal Commission of Health and Family Planning, Key Developing Disciplines Program, Shanghai Key disciplines program of Health and Family Planning and Shanghai Sailing Program.
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Other epigenetic regulators, including MECP2, EZH1/2, BRD4, SIRT1, KDM4D, and TET3, can contribute to chemically induced liver fibrosis.
“Other epigenetic regulators, such as methyl CpG binding protein 2 (MECP2), enhancer of zeste homolog 1/2 (EZH1/2), bromodomain-containing protein 4 (BRD4), Sirtuin 1 (SIRT1), lysine-specific demethylase 4D (KDM4D), and tet methylcytosine dioxygenase 3 (TET3), can contribute to chemically-induced liver fibrosis (174-178) (179, 180) (181).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [178]
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Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
Wang, S., & Friedman, S. L. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0759 · Cited by 158 · see citing works
- Authors
- Dong, F., Jiang, S., Li, J., Wang, Y., Zhu, L., Huang, Y., Jiang, X., Hu, X., Zhou, Q., Zhang, Z., & Bao, Z.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Shanghai Jiao Tong University (CN)
- Tongji Hospital (CN)
- Corresponding author
- Hu, Xiaona
- Zhou, Qi
- Zhang, Zhigang
- Bao, Zhijun
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 39
- Pages
- 472-483
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC6354657
- OpenAlex
- W2952302425
- Cited by
- 40
- References
- 36
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 10 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 1
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Shanghai New Hundred Talents Program (XBR2013091)
- Shanghai Municipal Commission of Health and Family Planning
- Key Developing Disciplines Program (2015ZB0501)
- Shanghai Key disciplines program of Health and Family Planning (2017ZZ02010)
- Shanghai Sailing Program (17YF1405200)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- KDM4D, histone demethylase, liver fibrosis, hepatic stellate cell activation, TLR4, NF-κB signaling, H3K9 demethylation, epigenetic regulation, liver fibrogenesis, collagen deposition, TLR4/NF-κB signaling
- MeSH terms
- Animals, Carbon Tetrachloride, Cell Line, Histones, Humans, Liver Cirrhosis, Male, Thioacetamide, Transcription, Genetic, Signal Transduction, Up-Regulation, Epigenesis, Genetic, Toll-Like Receptor 4, Mice, Rats, Gene Regulatory Networks, Hepatic Stellate Cells, Jumonji Domain-Containing Histone Demethylases
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