PMID- 30282980 OWN - NLM STAT- MEDLINE DCOM- 20191114 LR - 20231213 IS - 2041-4889 (Electronic) VI - 9 IP - 10 DP - 2018 Oct 3 TI - Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis. PG - 1021 LID - 10.1038/s41419-018-1032-9 [doi] LID - 1021 AB - 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-beta1-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. FAU - Chen, Xin AU - Chen X AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Li, Wan-Xia AU - Li WX AD - Dept of Pharmacy, Anqing Municipal Hospital, Anqing, 246000, China. FAU - Chen, Yu AU - Chen Y AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Li, Xiao-Feng AU - Li XF AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Li, Hai-Di AU - Li HD AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Huang, Hui-Min AU - Huang HM AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Bu, Fang-Tian AU - Bu FT AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Pan, Xue-Yin AU - Pan XY AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Yang, Yang AU - Yang Y AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Huang, Cheng AU - Huang C AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Meng, Xiao-Ming AU - Meng XM AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. FAU - Li, Jun AU - Li J AD - School of Pharmacy, Anhui Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, 230032, China. lj@ahmu.edu.cn. AD - The key laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei, 230032, China. lj@ahmu.edu.cn. AD - Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China. lj@ahmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181003 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Membrane Proteins) RN - 0 (Sun2 protein, mouse) RN - 0 (Telomere-Binding Proteins) RN - CL2T97X0V0 (Carbon Tetrachloride) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Carbon Tetrachloride/pharmacology MH - Cell Line MH - Cell Proliferation/drug effects MH - DNA (Cytosine-5-)-Methyltransferases/metabolism MH - DNA Methylation/drug effects/*physiology MH - Hepatic Stellate Cells/drug effects/*metabolism MH - Liver/drug effects/*metabolism MH - Liver Cirrhosis/*metabolism MH - Male MH - Membrane Proteins/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - Phosphorylation/drug effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction/drug effects/physiology MH - Telomere-Binding Proteins/*metabolism MH - DNA Methyltransferase 3B PMC - PMC6170444 COIS- The authors declare that they have no conflict of interest. EDAT- 2018/10/05 06:00 MHDA- 2019/11/15 06:00 PMCR- 2018/10/03 CRDT- 2018/10/05 06:00 PHST- 2018/03/23 00:00 [received] PHST- 2018/08/20 00:00 [accepted] PHST- 2018/07/18 00:00 [revised] PHST- 2018/10/05 06:00 [entrez] PHST- 2018/10/05 06:00 [pubmed] PHST- 2019/11/15 06:00 [medline] PHST- 2018/10/03 00:00 [pmc-release] AID - 10.1038/s41419-018-1032-9 [pii] AID - 1032 [pii] AID - 10.1038/s41419-018-1032-9 [doi] PST - epublish SO - Cell Death Dis. 2018 Oct 3;9(10):1021. doi: 10.1038/s41419-018-1032-9.