International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


PLENARY PRESENTATION

WEDNESDAY 12 NOVEMBER
11:30 – 12:00 HRS

RATIONAL DESIGN OF MOUSE MODELS TO STUDY FOLATE-ASSOCIATED PATHOLOGIES

Patrick Stover
Cornell University

Nutritional and genetic epidemiological studies indicate strong associations between disruption of folate metabolism, induced by vitamin deficiency and/or penetrant SNPs, and risk for pathologies and developmental anomalies including neural tube defects and cancers. The molecular mechanism(s) that account for folate-pathology associations are unknown, and animal models developed to date have not advanced our understanding. Folate metabolism is necessary for the synthesis of nucleotides (purines and dTMP) and S-adenosylmethionine and thereby influences both DNA methylation density and uracil content. Both DNA uracil content and methylation density affect DNA stability, and DNA methylation also regulates the expression of many genes. It is not known if the associations between folate and pathology risk result from altered SAM synthesis and/or dTMP synthesis. We have demonstrated that the enzyme cytoplasmic serine hydroxymethyltransferase (cSHMT) is a metabolic switch that directs the flux of folate-activated one-carbon units between dTMP and SAM biosynthetic pathways, and is expressed in tissues that are associated with folate-related pathologies. The expression of cSHMT is dynamically regulated by several nutrients including iron/ferritin, and therefore the cSHMT-mediated metabolic switch is likely involved in the etiology of folate-related pathologies and may be a target for disease prevention through diet. We have generated gain-of-function, loss-of-function, and dominant negative mouse models to determine the effect of altered cSHMT expression on 1. - metabolism, 2.- genome integrity and expression and 3.- disease risk. These models are establishing the role of diet in regulating cSHMT, and the effects of diet-induced changes in cSHMT activity on genome integrity, expression and risk for folate-related pathologies.


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