title: Murine diet/tissue and human brain tumorigenesis alter Mthfr/MTHFR 5'-end methylation.
abstract: Polymorphisms and decreased activity of methylenetetrahydrofolate reductase (MTHFR) are linked to disease, including cancer. However, epigenetic regulation has not been thoroughly studied. Our goal was to generate DNA methylation profiles of murine/human MTHFR gene regions and examine methylation in brain and liver tumors. Pyrosequencing in four murine tissues revealed minimal DNA methylation in the CpG island. Higher methylation was seen in liver or intestine in the CpG island shore 5' to the upstream translational start site or in another region 3' to the downstream start site. In the latter region, there was negative correlation between expression and methylation. Three orthologous regions were investigated in human MTHFR, as well as a fourth region between the two translation start sites. We found significantly increased methylation in three regions (not the CpG island) in pediatric astrocytomas compared with control brain, with decreased expression in tumors. Methylation in hepatic carcinomas was also increased in the three regions compared with normal liver, but the difference was significant for only one CpG. This work, the first overview of the Mthfr/MTHFR epigenetic landscape, suggests regulation through methylation in some regions, demonstrates increased methylation/decreased expression in pediatric astrocytomas, and should serve as a resource for future epigenetic studies.
authors.affiliation: Departments of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Bloc E, Rm E M0.3211, Montreal, H4A 3J1, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Lévesque
authors.affiliation: Departments of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Bloc E, Rm E M0.3211, Montreal, H4A 3J1, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Leclerc
authors.affiliation: Division of Experimental Medicine, Departments of Pediatrics and Human Genetics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Montreal, H4A 3J1, Canada.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gayden
authors.affiliation: Department of Surgery, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Montreal, H4A 3J1, Canada.
authors.forename: Anthoula
authors.initials: A
authors.lastname: Lazaris
authors.affiliation: Division of Experimental Medicine, Departments of Pediatrics and Human Genetics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Montreal, H4A 3J1, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: De Jay
authors.affiliation: Department of Surgery, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Montreal, H4A 3J1, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Petrillo
authors.affiliation: Department of Surgery, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Montreal, H4A 3J1, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Metrakos
authors.affiliation: Division of Experimental Medicine, Departments of Pediatrics and Human Genetics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Montreal, H4A 3J1, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Departments of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Bloc E, Rm E M0.3211, Montreal, H4A 3J1, Canada. rima.rozen@mcgill.ca.
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D004032:Diet; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000378:metabolism
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2)