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Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis

Hepatic myofibroblasts, activated hepatic stellate cells (HSCs), are the main cell type of extracellular matrix (ECM) deposition during hepatic fibrosis. Aberrant DNA methylation-regulated HSCs activation in liver fibrogenesis has been reported, but the functional roles and mechanisms of DNA methyla...

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Autores principales: Chen, Xin, Li, Wan-Xia, Chen, Yu, Li, Xiao-Feng, Li, Hai-Di, Huang, Hui-Min, Bu, Fang-Tian, Pan, Xue-Yin, Yang, Yang, Huang, Cheng, Meng, Xiao-Ming, Li, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170444/
https://www.ncbi.nlm.nih.gov/pubmed/30282980
http://dx.doi.org/10.1038/s41419-018-1032-9
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author Chen, Xin
Li, Wan-Xia
Chen, Yu
Li, Xiao-Feng
Li, Hai-Di
Huang, Hui-Min
Bu, Fang-Tian
Pan, Xue-Yin
Yang, Yang
Huang, Cheng
Meng, Xiao-Ming
Li, Jun
author_facet Chen, Xin
Li, Wan-Xia
Chen, Yu
Li, Xiao-Feng
Li, Hai-Di
Huang, Hui-Min
Bu, Fang-Tian
Pan, Xue-Yin
Yang, Yang
Huang, Cheng
Meng, Xiao-Ming
Li, Jun
author_sort Chen, Xin
collection PubMed
description Hepatic myofibroblasts, activated hepatic stellate cells (HSCs), are the main cell type of extracellular matrix (ECM) deposition during hepatic fibrosis. Aberrant DNA methylation-regulated HSCs activation in liver fibrogenesis has been reported, but the functional roles and mechanisms of DNA methylation in hepatic fibrosis remain to be elucidated. In the present study, reduced representation bisulfite sequencing (RRBS) analysis of primary HSCs revealed hypermethylation patterns in hepatic fibrosis. Interestingly, we found SAD1/UNC84 domain protein-2 (SUN2) gene hypermethylation at CpG sites during liver fibrogenesis in mice with CCl(4)-induced hepatic fibrosis, which was accompanied by low expression of SUN2. In vivo overexpression of SUN2 following adeno-associated virus-9 (AAV9) administration inhibited CCl(4)-induced liver injury and reduced fibrogenesis marker expression. Consistently, in vitro experiments showed that enforced expression of SUN2 suppressed HSCs activation and exerted anti-fibrogenesis effects in TGF-β1-activated HSC-T6 cells. In addition, the signaling mechanisms related to SUN2 expression were investigated in vivo and in vitro. Methyltransferase-3b (DNMT3b) is the principal regulator of SUN2 expression. Mechanistically, inhibition of protein kinase B (AKT) phosphorylation may be a crucial pathway for SUN2-mediated HSCs activation. In conclusion, these findings provide substantial new insights into SUN2 in hepatic fibrosis.
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spelling pubmed-61704442018-10-09 Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis Chen, Xin Li, Wan-Xia Chen, Yu Li, Xiao-Feng Li, Hai-Di Huang, Hui-Min Bu, Fang-Tian Pan, Xue-Yin Yang, Yang Huang, Cheng Meng, Xiao-Ming Li, Jun Cell Death Dis Article Hepatic myofibroblasts, activated hepatic stellate cells (HSCs), are the main cell type of extracellular matrix (ECM) deposition during hepatic fibrosis. Aberrant DNA methylation-regulated HSCs activation in liver fibrogenesis has been reported, but the functional roles and mechanisms of DNA methylation in hepatic fibrosis remain to be elucidated. In the present study, reduced representation bisulfite sequencing (RRBS) analysis of primary HSCs revealed hypermethylation patterns in hepatic fibrosis. Interestingly, we found SAD1/UNC84 domain protein-2 (SUN2) gene hypermethylation at CpG sites during liver fibrogenesis in mice with CCl(4)-induced hepatic fibrosis, which was accompanied by low expression of SUN2. In vivo overexpression of SUN2 following adeno-associated virus-9 (AAV9) administration inhibited CCl(4)-induced liver injury and reduced fibrogenesis marker expression. Consistently, in vitro experiments showed that enforced expression of SUN2 suppressed HSCs activation and exerted anti-fibrogenesis effects in TGF-β1-activated HSC-T6 cells. In addition, the signaling mechanisms related to SUN2 expression were investigated in vivo and in vitro. Methyltransferase-3b (DNMT3b) is the principal regulator of SUN2 expression. Mechanistically, inhibition of protein kinase B (AKT) phosphorylation may be a crucial pathway for SUN2-mediated HSCs activation. In conclusion, these findings provide substantial new insights into SUN2 in hepatic fibrosis. Nature Publishing Group UK 2018-10-03 /pmc/articles/PMC6170444/ /pubmed/30282980 http://dx.doi.org/10.1038/s41419-018-1032-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chen, Xin
Li, Wan-Xia
Chen, Yu
Li, Xiao-Feng
Li, Hai-Di
Huang, Hui-Min
Bu, Fang-Tian
Pan, Xue-Yin
Yang, Yang
Huang, Cheng
Meng, Xiao-Ming
Li, Jun
Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis
title Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis
title_full Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis
title_fullStr Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis
title_full_unstemmed Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis
title_short Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis
title_sort suppression of sun2 by dna methylation is associated with hscs activation and hepatic fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170444/
https://www.ncbi.nlm.nih.gov/pubmed/30282980
http://dx.doi.org/10.1038/s41419-018-1032-9
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