Daniel S Lupu 1, Luz D. Orozco 2, Ying Wang 3 and Steven H Zeisel 1 (2016). The impact of choline oxidation pathway on liver methylation potential. The FASEB Journal, 30(1)
1. Nutrition, University of North Carolina, Nutrition Research Institute, Kannapolis, NC
2. Cell and Developmental Biology, University of California, Los Angeles, CA
3. Clinical Nutrition, Shanghai Jiao Tong University School of Medicine, Shanghai, China, People’s Republic of
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.