Abstract
Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, there has been a significant progress in their understanding. The picture emerging from the studies of homocysteine (Hcy) metabolism and pathophysiology is a complex one, as Hcy and its metabolites affect biomolecules and processes in a tissue- and sex-specific manner. Because of their connection to one carbon metabolism and editing mechanisms in protein biosynthesis, Hcy and its metabolites impair epigenetic control of gene expression mediated by DNA methylation, histone modifications, and non-coding RNA, which underlies the pathology of human disease. In this review we summarize the recent evidence showing that epigenetic dysregulation of gene expression, mediated by changes in DNA methylation and histone N-homocysteinylation, is a pathogenic consequence of HHcy in many human diseases. These findings provide new insights into the mechanisms of human disease induced by Hcy and its metabolites, and suggest therapeutic targets for the prevention and/or treatment.
Highlights
Hyperhomocysteinemia (HHcy), a medical condition of elevated homocysteine (Hcy) concentration in the plasma, usually defined as >15 μM [1,2], is prevalent in the general population and may have severe implications for the human health [3]
In this review we summarize the recent progress in studies of epigenetic dysregulation of gene expression by HHcy and its role in the etiology of human disease
HHcy-induced atherosclerosis in ApoE-/- mice is mediated by decreased DNA methylation and increased fatty acid-binding protein 4 (FABP4) expression (Table 2)
Summary
Hyperhomocysteinemia (HHcy), a medical condition of elevated homocysteine (Hcy) concentration in the plasma, usually defined as >15 μM [1,2], is prevalent in the general population and may have severe implications for the human health [3]. By being a byproduct of cellular methylation reactions, is a sensitive marker of one-carbon metabolism important for multiple physiological processes, including epigenetic regulation [26,27]. A novel mechanism of epigenetic dysregulation in HHcy has been revealed by studies of Hcy-editing by MARS during protein biosynthesis [30], which generates HTL (Figure 1). In this review we summarize the recent progress in studies of epigenetic dysregulation of gene expression by HHcy and its role in the etiology of human disease. As discussed the changes in gene expression induced by HHcy involve epigenetic mechanisms: DNA methylation and histone modifications, including acetylation, methylation, and N-homocysteinylation (Figure 1) (Tables 1 and 2). ↑5-mC in brain DNA from CBS+/−, + Met mice; tended to decrease in FA-supplemented mice
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