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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 (FPGS\n                    <jats:sup>ko<\/jats:sup>\n                    ) 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\n                    <jats:italic>NANOG<\/jats:italic>\n                    , octamer\u2010binding transcription factor 4, and sex\u2010determining region Y\u2010box 2 levels were increased in the mutant, consistent with the transition to a stem cell\u2010like state. Gene expression and metabolite data also indicate a major change in Glu and GABA metabolism. In the appropriate medium, FPGS\n                    <jats:sup>ko<\/jats:sup>\n                    cells can differentiate to produce mainly cells with characteristics of either neural stem cells or cardiomyocytes.\u2014Srivastava, 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. FASEB J. 33, 13747\u201013761 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201901721r","type":"journal-article","created":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T21:28:20Z","timestamp":1570224500000},"page":"13747-13761","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Elimination of human folypolyglutamate synthetase alters programming and plasticity of somatic cells"],"prefix":"10.1096","volume":"33","author":[{"given":"Avinash C.","family":"Srivastava","sequence":"first","affiliation":[{"name":"Department of Diabetes Complications and Metabolism City of Hope National Medical Center Duarte California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yesenia 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