Altered methylation of specific DNA loci in the liver ofBhmt-null mice results in repression ofIqgap2andF2rl2and is associated with development of preneoplastic foci.
Folate B12-dependent remethylation of homocysteine 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 C57Bl/6JBhmt(betaine-homocysteine methyltransferase)-null mice at age 4, 12, 24, and 52 wk (N= 8) and observed elevation ofS-adenosylhomocysteine concentrations and development of preneoplastic foci in the liver (increased placental glutathioneS-transferase and cytokeratin 8-18 activity; starting at 12 wk). At 4 wk, we identified 63 differentially methylated CpGs (DMCs; false discovery rate < 5%) proximal to 81 genes (across 14 chromosomes), of which 18 were differentially expressed. Of these DMCs, 52% were located in one 15.5-Mb locus on chromosome 13, which encompassed theBhmtgene and defined a potentially sensitive region with mostly decreased methylation. Analyzing Hybrid Mouse Diversity Panel data, which consisted of 100 inbred strains of mice, we identified 97 DMCs that were affected byBhmtgenetic variation in the same region, with 7 overlapping those found inBhmt-null mice (P< 0.001). At all time points, we found a hypomethylated region mapping toIqgap2(IQ motif-containing GTPase activating protein 2) andF2rl2(proteinase-activated receptor-3), 2 genes that were also silenced and underexpressed, respectively.-Lupu, D. S., Orozco, L. D., Wang, Y., Cullen, J. M., Pellegrini, M., Zeisel, S. H. Altered methylation of specific DNA loci in the liver ofBhmt-null mice results in repression ofIqgap2andF2rl2and is associated with development of preneoplastic foci.
Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina, USA.
Daniel S
DS
Lupu
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Luz D
LD
Orozco
Department of Clinical Nutrition, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, Shanghai, China.
Ying
Y
Wang
North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina, USA.
John M
JM
Cullen
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
Matteo
M
Pellegrini
Department of Nutrition, Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina, USA; steven_zeisel@unc.edu.
Steven H
SH
Zeisel
D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000172:deficiency / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation / Q000502:physiology; D005492:Folic Acid / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011230:Precancerous Conditions / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
C484416:Iqgap2 protein, mouse; D018179:Receptors, Thrombin; C105295:protease-activated receptor 3; D020703:ras GTPase-Activating Proteins; D004247:DNA; D005492:Folic Acid; D050940:Betaine-Homocysteine S-Methyltransferase; C494549:Bhmt protein, mouse; D005982:Glutathione Transferase
betaine; epigenetics; folate; methylome