Dysregulation of Epigenetic Mechanisms of Gene Expression in the Pathologies of Hyperhomocysteinemia

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.

Keywords: Alzheimer’s disease; DNA methylation; N-homocysteinylation; atherosclerosis; epigenetic; gene expression; histone; homocysteine thiolactone; hyperhomocysteinemia; miRNA.

Figure 1

Homocysteine (Hcy) metabolism. See text for description. Metabolites and enzymes related to epigenetics are highlighted in blue. AHCY, S-adenosylhomocysteine hydrolase; BHMT, betaine:Hcy methyltransferase; BLMH, bleomycin hydrolase; BPHL, biphenyl hydrolase like; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; DNMTs, DNA methyltransferases; HMT, histone methyltransferase; HTL, homocysteine thiolactone; MARS, Met-tRNA synthetase; mHistone, methylated histone; MTHFR, 5,10-methylenetetrahydrofolate reductase; MS, Met synthase; PON1, paraoxonase 1; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SHMT, serine hydroxymethyltransferase.

Figure 2

The top network of HTL-responsive genes: Cardiovascular disease, cardiac infarction, skeletal and muscular system development and function. The major nodes in the network contain histones and other chromatin-related proteins (reproduced with permission from reference [38]).