Cystathionine ?-lyase downregulation contributes to hepatocyte injury and dysfunction via multiple signaling pathways by regulation of histone lysine methylation

Chronic liver disease (CLD) is prevalent globally. We sought to elucidate the molecular mechanisms governing the progress of CLD. We confirmed hepatic cystathionine ?-lyase (Cth) expression was significantly down-regulated in some CLDs. Therefore, we subsequently investigated the roles of Cth gene in the regulation of hepatic function and underlying mechanisms by using Cth knockout mice. Furthermore, we found that Cth deficiency resulted in one-carbon unit reprogramming, and betaine was one of key metabolites in one-carbon reprogramming, which caused changed histone lysine methylation and thereby leading to dysregulation of PPARa, PGC-1a, IRF8 and IRF9, the transcriptional factors governing metabolism, mitochondrial function and apoptosis. Our data immediately highlight a new potential target for therapy of some CLDs. Overall design: To investigate the role of CTH in chronic liver disease, liver tissues from WT mice, CTH-deficient mice, and CTH-deficient mice supplemented with betaine were analyzed by RNA-Seq.