biostudies-literatureTian SThe Strategic Priority Research Program of the Chinese Academy of SciencesThe National Natural Science Foundation of ChinaThe Program for Guangdong Introducing Innovative and Entrepreneurial TeamsThe Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and TechnologyThe National Key R&D Program of Chinae201900413https://www.ebi.ac.uk/biostudies/studies/S-EPMC6765226biostudies-literatureUnknown2(5)Metabolic remodelling has emerged as critical for stem cell pluripotency; however, the underlying mechanisms have yet to be fully elucidated. Here, we found that the glycine cleavage system (GCS) is highly activated to promote stem cell pluripotency and during somatic cell reprogramming. Mechanistically, we revealed that the expression of Gldc, a rate-limiting GCS enzyme regulated by Sox2 and Lin28A, facilitates this activation. We further found that the activated GCS catabolizes glycine to fuel H3K4me3 modification, thus promoting the expression of pluripotency genes. Moreover, the activated GCS helps to cleave excess glycine and prevents methylglyoxal accumulation, which stimulates senescence in stem cells and during reprogramming. Collectively, our results demonstrate a novel mechanism Life science allianceGlycine cleavage system determines the fate of pluripotent stem cells via the regulation of senescence and epigenetic modifications.PMC67652262017ZT07S05481525022, 31571472, 81530076, and 81821001XDPB102017FXZY0042018YFA0800300, 2018YFA0107103, and 2017YFA0205600Gao PFeng JCao YZhang HTian SCai YShen SZhong XYan RYang DWang LfalseGlycine cleavage system determines the fate of pluripotent stem cells via the regulation of senescence and epigenetic modifications.Metabolic remodelling has emerged as critical for stem cell pluripotency; however, the underlying mechanisms have yet to be fully elucidated. Here, we found that the glycine cleavage system (GCS) is highly activated to promote stem cell pluripotency and during somatic cell reprogramming. Mechanistically, we revealed that the expression of Gldc, a rate-limiting GCS enzyme regulated by Sox2 and Lin28A, facilitates this activation. We further found that the activated GCS catabolizes glycine to fuel H3K4me3 modification, thus promoting the expression of pluripotency genes. Moreover, the activated GCS helps to cleave excess glycine and prevents methylglyoxal accumulation, which stimulates senescence in stem cells and during reprogramming. Collectively, our results demonstrate a novel mechanism 2019-01-01T00:00:00Z2019 Oct2026-04-29T15:01:48.06Z2019-10-11T07:12:32ZS-EPMC67652263156219210.26508/lsa.201900413