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

ABSTRACT: 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.

SUBMITTER: Srivastava AC

PROVIDER: S-EPMC6894074 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Srivastava Avinash C AC Thompson Yesenia Guadalupe YG Singhal Jyotsana J Stellern Jordan J Srivastava Anviksha A Du Juan J O'Connor Timothy R TR Riggs Arthur D AD

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20191004 12

Folates are vital cofactors for the regeneration of <i>S</i>-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 metaboli ...[more]

PMID: 31585510

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

Publications

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

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