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KDM4C represses liver fibrosis by regulating H3K9me3 methylation of ALKBH5 and m6A methylation of snail1 mRNA.
Zhou, Hua Ying; Wang, Bing Qing; Chen, Meng Xuan; Wang, Yi Fan; Jiang, Yong Fang; Ma, Jing.
Afiliación
  • Zhou HY; Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
  • Wang BQ; Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
  • Chen MX; Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
  • Wang YF; Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
  • Jiang YF; Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
  • Ma J; Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
J Dig Dis ; 25(5): 298-309, 2024 May.
Article en En | MEDLINE | ID: mdl-38938016
ABSTRACT

OBJECTIVE:

We aimed to disclose the molecular mechanism of snail1 in liver fibrosis.

METHODS:

Carbon tetrachloride (CCl4) was used to induce a liver fibrosis model in mice whereby serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated, and liver pathological alternations were assessed. Rat hepatic stellate cells (HSC-T6) were irritated with transforming growth factor (TGF)-ß1, followed by assessment of cell viability and migration. The levels of snail1, ALKBH5, and lysine specific demethylase 4C (KDM4C) were quantified by immunohistochemistry, western blot, or reverse transcription-quantitative polymerase chain reaction, in addition to α-smooth muscle actin (SMA), anti-collagen type I α1 (COL1A1), vimentin, and E-cadherin. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and RNA stability were evaluated to determine the relationship between ALKBH5 and snail1. Changes in KDM4C-bound ALKBH5 promoter and enrichment of histone H3 lysine 9 trimethylation (H3K9me3) at the ALKBH5 promoter were determined using chromatin immunoprecipitation.

RESULTS:

In fibrosis mice, snail1 was upregulated while ALKBH5 and KDM4C were downregulated. KDM4C overexpression reduced serum ALT and AST levels, liver injury, and α-SMA, COL1A1 and VIMENTIN expressions but increased E-cadherin expression. However, the aforementioned trends were reversed by concurrent overexpression of snail1. In HSC-T6 cells exposed to TGF-ß1, ALKBH5 overexpression weakened cell viability and migration, downregulated α-SMA, COL1A1 and VIMENTIN, upregulated E-CADHERIN, and decreased m6A modification of snail1 and its mRNA stability. KDM4C increased ALKBH5 expression by lowering H3K9me3 level, but inhibited HSC-T6 cell activation by regulating the ALKBH5/snail1 axis.

CONCLUSION:

KDM4C decreases H3K9me3 methylation to upregulate ALKBH5 and subsequently inhibits snail1, ultimately impeding liver fibrosis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Estrelladas Hepáticas / Desmetilasa de ARN, Homólogo 5 de AlkB / Factores de Transcripción de la Familia Snail / Cirrosis Hepática Límite: Animals Idioma: En Revista: J Dig Dis Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Estrelladas Hepáticas / Desmetilasa de ARN, Homólogo 5 de AlkB / Factores de Transcripción de la Familia Snail / Cirrosis Hepática Límite: Animals Idioma: En Revista: J Dig Dis Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia