One-Carbon Metabolism and Hepatocellular Carcinoma Public Deposited

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  • March 22, 2019
Creator
  • Lupu, Daniel
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
Abstract
  • Folate-B12-dependent remethylation of homocysteine (Hcy) is important, but less is understood about the importance of the alternative betaine-dependent methylation pathway (catalyzed by betaine-homocysteine methyltransferase; BHMT) for establishing and maintaining adequate DNA methylation across the genome. We studied Bhmt-null mice at 4, 12, 24, and 52 weeks of age and observed elevation of S-adenosylhomocysteine (AdoHcy) concentrations and development of preneoplastic foci in liver (increased placental glutathione S-transferase activity; GST-P) starting at 12 weeks. At 4 weeks we identified 63 differentially methylated CpGs (DMCs; FDR < 5%) proximal to 81 genes (across 14 chromosomes), 18 of which were differentially expressed. 52% of these DMCs were located in one 15.5 Mb locus on chromosome 13, encompassing the Bhmt gene and defining a potentially sensitive region with mostly decreased methylation. Analyzing Hybrid Mouse Diversity Panel (HMDP) data (consisting of over 100 inbred strains of mice), we identified 97 DMCs affected by Bhmt genetic variation in the same region, with 7 overlapping those found in the Bhmt-null mice (p < 0.001). At all time points, we found a hypomethylated region mapping to IQ motif-containing GTPase activating protein 2 (Iqgap2) and Proteinase-Activated Receptor-3 (F2rl2), two genes that were also silenced and under-expressed, respectively. For the first time we show that silencing of Bhmt, one of the two key controllers of methyl flux metabolism, is associated with DNA methylation dysregulation, culminating in transcriptomic changes in the liver. Considering the potential impact of Iqgap2 and F2rl2 in hepatocellular carcinoma (HCC) initiation and progression, future studies addressing their response to Bhmt and one-carbon metabolism changes in people are needed.
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  • In Copyright
Advisor
  • Zeisel, Steven H.
  • Shen, Lanlan
  • Kaufman, David
  • Bataller, Ramon
  • Hursting, Stephen
  • Ideraabdullah, Folami
  • Coleman, William
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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