Elimination of human folypolyglutamate synthetase alters programming and plasticity of somatic cells.

Folates are vital cofactors for the regeneration of S-adenosyl methionine, which is the methyl source for DNA methylation, protein methylation, and other aspects of one-carbon (C1) metabolism. Thus, folates are critical for establishing and preserving epigenetic programming. Folypolyglutamate synthetase (FPGS) is known to play a crucial role in the maintenance of intracellular folate levels. Therefore, any modulation in FPGS is expected to alter DNA methylation and numerous other metabolic pathways. To explore the role of polyglutamylation of folate, we eliminated both isoforms of FPGS in human cells (293T), producing FPGS knockout (FPGSko) cells. The elimination of FPGS significantly decreased cell proliferation, with a major effect on oxidative phosphorylation and a lesser effect on glycolysis. We found a substantial reduction in global DNA methylation and noteworthy changes in gene expression related to C1 metabolism, cell division, DNA methylation, pluripotency, Glu metabolism, neurogenesis, and cardiogenesis. The expression levels of NANOG, octamer-binding transcription factor 4, and sex-determining region Y-box 2 levels were increased in the mutant, consistent with the transition to a stem cell-like state. Gene expression and metabolite data also indicate a major change in Glu and GABA metabolism. In the appropriate medium, FPGSko cells can differentiate to produce mainly cells with characteristics of either neural stem cells or cardiomyocytes.-Srivastava, A. C., Thompson, Y. G., Singhal, J., Stellern, J., Srivastava, A., Du, J., O'Connor, T. R., Riggs, A. D. Elimination of human folypolyglutamate synthetase alters programming and plasticity of somatic cells.

Agricultural Exposures and Breast Cancer Among Latina in the San Joaquin Valley of California.

OBJECTIVE: The aim of this study was to assess the role of agricultural work, pesticide exposure, and age at first farm labor exposure in breast cancer (BC) risk among Hispanic women in Central California. METHODS: A BC case control study was conducted. Latina BC cases were identified through the California Cancer Registry and controls were recruited. Both cases and controls completed a detailed questionnaire. Pesticide exposure data were obtained by linking the crops, work locations, and dates worked in specific farm jobs with the California Department of Pesticide Regulation (DPR) Pesticide Use Reports (PUR). RESULTS: Chemicals associated with BC risk included organophosphates, organochlorines, and a phthalimide, Captan. Age at first work in farm labor was younger in cases than controls (P = 0.03). CONCLUSIONS: Agricultural work may be associated with the increased BC risk in female Hispanic farm workers.