PMID- 29415998 OWN - NLM STAT- MEDLINE DCOM- 20190801 LR - 20190801 IS - 2041-4889 (Electronic) VI - 9 IP - 2 DP - 2018 Feb 7 TI - Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver. PG - 169 LID - 10.1038/s41419-017-0216-z [doi] LID - 169 AB - Elevated homocysteine (Hcy) levels have been reported to be involved in liver injury, and autophagy plays an important role in normal hepatic physiology and pathophysiology, but the mechanism underlying Hcy regulated autophagy is currently unknown. In this study, CBS(+/-) mice were fed with regular diet for 12 weeks to establish a hyperhomocysteinemia (HHcy) model and HL-7702 cells were treated with Hcy, we found that Hcy increases autophagy and aggravates liver injury by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo and in vitro. Overexpression of CFTR inhibited the formation of autophagosomes and the expression of autophagy-related proteins BECN1, LC3-II/I and Atg12, while the expression of p62 increased in Hcy-treated hepatocytes and CBS(+/-) mice injected with lentivirus expressing CFTR. Further study showed that CFTR expression is regulated by the interaction of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), which, respectively, regulate DNA methylation and histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, our study showed that Hcy activates autophagy by inhibition of CFTR expression via interaction between H3K27me3 and DNA methylation in the mouse liver. These findings provide new insight into the mechanism of Hcy-induced autophagy in liver injury. FAU - Yang, Anning AU - Yang A AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. FAU - Jiao, Yun AU - Jiao Y AD - Ningxia Medical University General Hospital, Yinchuan, 750004, China. FAU - Yang, Songhao AU - Yang S AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. FAU - Deng, Mei AU - Deng M AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. FAU - Yang, Xiaoling AU - Yang X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. FAU - Mao, Caiyan AU - Mao C AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. FAU - Sun, Yue AU - Sun Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. FAU - Ding, Ning AU - Ding N AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. FAU - Li, Nan AU - Li N AD - Pharmacy college, Ningxia Medical University, Yinchuan, 750004, China. FAU - Zhang, Minghao AU - Zhang M AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. FAU - Jin, Shaoju AU - Jin S AD - Pharmacy college, Ningxia Medical University, Yinchuan, 750004, China. FAU - Zhang, Huiping AU - Zhang H AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. zhp19760820@163.com. AD - Ningxia Medical University General Hospital, Yinchuan, 750004, China. zhp19760820@163.com. FAU - Jiang, Yideng AU - Jiang Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China. jiangyd@nxmu.edu.cn. AD - Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China. jiangyd@nxmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180207 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Biomarkers) RN - 0 (Histones) RN - 0LVT1QZ0BA (Homocysteine) RN - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1) RN - EC 2.1.1.37 (Dnmt1 protein, mouse) RN - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein) RN - EC 4.2.1.22 (Cystathionine beta-Synthase) RN - K3Z4F929H6 (Lysine) MH - Animals MH - Autophagy/*drug effects MH - Biomarkers/metabolism MH - Cystathionine beta-Synthase/metabolism MH - Cystic Fibrosis Transmembrane Conductance Regulator/*metabolism MH - DNA (Cytosine-5-)-Methyltransferase 1/metabolism MH - DNA Methylation/drug effects/*genetics MH - Down-Regulation/drug effects/genetics MH - Enhancer of Zeste Homolog 2 Protein/metabolism MH - Hepatocytes/drug effects/metabolism MH - Histones/*metabolism MH - Homocysteine/*pharmacology MH - Lentivirus/metabolism MH - Liver/drug effects/*metabolism/ultrastructure MH - Lysine/*metabolism MH - Mice MH - Promoter Regions, Genetic/genetics PMC - PMC5833451 COIS- The authors declare that they have no conflict of interest. EDAT- 2018/02/09 06:00 MHDA- 2019/08/02 06:00 PMCR- 2018/02/07 CRDT- 2018/02/09 06:00 PHST- 2017/08/15 00:00 [received] PHST- 2017/12/13 00:00 [accepted] PHST- 2017/11/11 00:00 [revised] PHST- 2018/02/09 06:00 [entrez] PHST- 2018/02/09 06:00 [pubmed] PHST- 2019/08/02 06:00 [medline] PHST- 2018/02/07 00:00 [pmc-release] AID - 10.1038/s41419-017-0216-z [pii] AID - 216 [pii] AID - 10.1038/s41419-017-0216-z [doi] PST - epublish SO - Cell Death Dis. 2018 Feb 7;9(2):169. doi: 10.1038/s41419-017-0216-z.