Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver

Abstract

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.

DNA Hypomethylation of miR-30a Mediated the Protection of Hypoxia Postconditioning Against Aged Cardiomyocytes Hypoxia/Reoxygenation Injury Through Inhibiting Autophagy

“…Aberrant miRNA expression is often associated with epigenetic regulation such as DNA methylation and histone modifications. 15 DNA methylation is recognized as the most important epigenetic regulation for gene expression, 16 which is catalyzed by DNA methyltransferases (DNMTs). Among them, DNMT1 (maintenance DNMT), DNMT3a and DNMT3b (de novo DNMTs) are mainly responsible for modulating and maintaining DNA methylation levels of gene promoter.…”

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

“…In addition to attenuating both inflammation and endothelial cell dysfunction [ 262 , 277 ], lowering homocysteine levels induces changes in the availability of methyl donors by facilitating the conversion from homocysteine to methionine, which may help regulate DNA methylation status [ 264 , 278 , 279 , 280 , 281 ]. Hyperhomocysteinemia-induced vascular pathologies, such as atherosclerosis, inflammation, hypertension, and diabetes, are also associated with alteration of DNA methylation status [ 282 , 283 , 284 , 285 , 286 , 287 ]. The failure of many trials of homocysteine-reducing treatments for the prevention of aging-associated diseases indicates that the alteration of methyl group availability is not sufficient to alter DNA methylation status, and thereby suppress the progression of aging-associated pathologies [ 288 , 289 , 290 ].…”

Hydrogen sulfide improves postischemic neoangiogenesis in the hind limb of cystathionine-β-synthase mutant mice via PPAR-γ/VEGF axis

“…; Yang et al. ). Hence, in this study, we used CBS +/− mouse model to dissect the effect(s) of HHcy on neoangiogenesis in the skeletal muscle and evaluate whether exogenous administration of GYY4137 (an H 2 S donor) could improve this effect(s).…”

“…CBS is one of the key enzymes in the transsulfuration pathway, and heterozygous CBS deficiency (CBS+/À) has proved to be a useful model for analyzing the effects of mild to a severe endogenous elevation in the levels of Hcy (Familtseva et al 2014;Nandi and Mishra 2017;Narayanan et al 2013;Tyagi et al 2011Tyagi et al , 2012Watanabe et al 1995;Winchester et al 2018;Yang et al 2018). Hence, in this study, we used CBS +/À mouse model to dissect the effect(s) of HHcy on neoangiogenesis in the skeletal muscle and evaluate whether exogenous administration of GYY4137 (an H 2 S donor) could improve this effect(s).…”