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The impact of choline oxidation pathway on liver methylation potential
Author(s) -
Lupu Daniel S,
Orozco Luz D.,
Wang Ying,
Zeisel Steven H
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.912.10
Subject(s) - methylation , epigenetics , methyltransferase , dna methylation , transmethylation , choline , betaine , biology , gene , locus (genetics) , bisulfite sequencing , methionine , genetics , regulation of gene expression , cystathionine beta synthase , gene expression , biochemistry , amino acid
DNA methylation has an important role in transcriptional regulation of gene expression. The methylation potential is sustained through the transmethylation pathway by methionine synthase (MS) and betaine‐‐homocysteine S‐methyltransferase (BHMT) based on methyl donors 5‐methyl‐tetrahydrofolate (5‐CH3‐THF) and betaine, respectively. Substantial research has been done on the contribution of the folate pathway to the methylation potential but less is known about the impact of the choline oxidation pathway. The aim of this study was to assess the methylation potential and identify subsequent DNA methylation and gene expression changes in the livers of Bhmt ‐null mice fed a normal folate and choline diet. We found a 73% average decrease in hepatic S ‐adenosylmethionine (AdoMet)/ S ‐adenosylhomocysteine (AdoHcy) ratio sustained across multiple time points (4, 12, 24, and 52 weeks). Following reduced representation bisulfite sequencing (RRBS) at 4 weeks we found 63 highly significant (FDR < 5%) differentially methylated CpGs across 14 chromosomes, out of which 33 CpGs are spanning a 15 mb locus in chromosome 13 in the vicinity of the Bhmt gene, defining a potentially sensitive region with mostly decreased methylation. These differentially methylated sites correspond to 81 genes, out of which 18 are differentially expressed. Studies are ongoing to determine if chromosome 13 locus methylation changes represent a genetic‐epigenetic interaction artefact or a sensitive long range epigenetic region. Preliminary data indicates that the choline oxidation pathway is an important source for maintaining the methyl pool required for DNA methylation. Support or Funding Information University of North Carolina, Nutrition Research Institute funds and NIH DK056350Differential methylation in the Bhmt‐null vs WT mouse liver in the chromosome 13 locus