Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia

Diego Ingrosso, Amelia Cimmino, Alessandra F. Perna, Lucia Masella, Natale G. De Santo, Maria Luigia De Bonis, Marcella Vacca, Maurizio D'Esposito, Michele D'Urso, Patrizia Galletti, Vincenzo Zappia

Research output: Contribution to journalArticle

Abstract

Background: Hyperhomocysteinaemia occurs in several genetically determined and acquired disorders and is highly prevalent in patients with uraemia. In these disorders, homocysteine precursor S-adenosylhomocysteine, a powerful competitive inhibitor of S-adenosylmethionine-dependent methyltransferases, is increased, suggesting unbalanced methylation. We aimed to investigate whether DNA hypomethylation is present in patients with uraemia who also have hyperhomocysteinaemia and whether regulation of specific classes of genes, dependent on DNA methylation, is compromised. Methods: We selected men with hyperhomocysteinaemia and uraemia who were having standard haemodialysis treatment, and compared them with healthy male controls. We measured the homocysteine concentration from plasma samples and obtained DNA and RNA samples from peripheral mononuclear cells. DNA methylation was assessed by cytosine extension assay and by Southern blotting. Allelic expression of pseudoautosomal and imprinted genes was investigated by analysis of suitable restriction fragment length polymorphisms. Findings: Total DNA hypomethylation was higher in patients than in controls (z score -4.593, p=0.0006) and allelic expression was changed in both sex-linked and imprinted genes. The shift from monoallelic to biallelic expression was dependent on homocysteine concentrations. Folate therapy, a common method to reduce hyperhomocysteinaemia, restored DNA methylation to normal levels and corrected the patterns of gene expression. Interpretation: Our results suggest that hyperhomocysteinaemia affects epigenetic control of gene expression, which can be reverted by folate treatment. Our data support the hypothesis that the toxic action of homocysteine can be mediated by macromolecule hypomethylation.

Original languageEnglish
Pages (from-to)1693-1699
Number of pages7
JournalLancet
Volume361
Issue number9370
DOIs
Publication statusPublished - May 17 2003

ASJC Scopus subject areas

  • Medicine(all)

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    Ingrosso, D., Cimmino, A., Perna, A. F., Masella, L., De Santo, N. G., De Bonis, M. L., Vacca, M., D'Esposito, M., D'Urso, M., Galletti, P., & Zappia, V. (2003). Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet, 361(9370), 1693-1699. https://doi.org/10.1016/S0140-6736(03)13372-7