S-adenosylhomocysteine hydrolase deficiency exacerbates clonal 1 hematopoiesis and atherosclerosis via epigenetic regulation of inflammation [Bisulfite-Seq]
Clonal hematopoiesis of indeterminate potential (CHIP) has been found to be associated with atherosclerotic cardiovascular disease (ASCVD). S-adenosylhomocysteine (SAH) is hydrolyzed by SAH hydrolase (SAHH) to homocysteine and adenosine. High levels of SAH and homocysteine has been considered as risk factors of ASCVD. However,  the effect and mechanism of SAHH deficiency on clonal hematopoiesis in atherogenesis is still unknown. Now we demonstrated that heterozygote knockout of SAHH accelerated clonal expansion of hematopoietic cells and promoted the development of atherosclerosis. Specifically,  myeloid cells-deficient SAHH was sufficient to promote the clonal hematopoiesis in atherogenesis. SAHH deficiency promoted proinflammatory genes expression in LPS/IFN-?–stimulated macrophages. Mechanistically,  SAHH ablation led to SAH accumulation and inhibited DNMT3a-mediated methylation of Nfkb2 and increased its transcriptional activation. On the contrary,  SAHH deficiency resulted in DNMT3c-mediated hypermethylation of PPARg and repressed its expression,  which is a negative regulator of Nfkb2-IL6 pathway. Furthermore,  SAHH deletion induced downregulation of adenosine-AMPK-TET2 and reduced recruitment of HDAC2 and DNMT3a to activate the expression of NFkb2. Knockdown of NFkb2 or IL6 neutralizing antibody repressed inflammation and alleviated SAHH deficiency-accelerated clonal hematopoiesis and atherosclerosis. Finally,  high plasma SAH levels were positively associated with IL6 and risk of CHIP in patients with CAD. Overall,  these findings reveal that SAHH deficiency accelerated clonal hematopoiesis and atherosclerosis via epigenetic regulation of inflammation. Overall design: Bisulfite-Seq from mouse peritoneal macrophages and their knockdown derivatives (SAHH-KO) after treatment with IFN-? and LPS.