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Murine diet/tissue and human brain tumorigenesis alter Mthfr/MTHFR 5′-end methylation

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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.

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Acknowledgments

This work was supported by the Canadian Institutes of Health Research (Grant No. MOP 43232 to RR). NL was supported by a Fellowship from the Fonds de Recherche du Québec - Santé and the RI-MUHC Desjardins Fellowship. The Research Institute is supported by a Centres Grant from the Fonds de Recherche du Québec - Santé.

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Authors and Affiliations

  1. 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

    Nancy Lévesque, Daniel Leclerc & Rima Rozen

  2. 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

    Tenzin Gayden, Nicolas De Jay & Nada Jabado

  3. Department of Surgery, The Research Institute of the McGill University Health Centre, McGill University, 1001 Décarie Blvd., Montreal, H4A 3J1, Canada

    Anthoula Lazaris, Stephanie Petrillo & Peter Metrakos

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  1. Nancy Lévesque
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  2. Daniel Leclerc
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  3. Tenzin Gayden
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Correspondence to Rima Rozen.

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Lévesque, N., Leclerc, D., Gayden, T. et al. Murine diet/tissue and human brain tumorigenesis alter Mthfr/MTHFR 5′-end methylation. Mamm Genome 27, 122–134 (2016). https://doi.org/10.1007/s00335-016-9624-0

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  • DOI: https://doi.org/10.1007/s00335-016-9624-0

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