Glycine decarboxylase regulates the maintenance and induction of pluripotency via metabolic control

Kang, Phil Jun; Zheng, Jie; Lee, Gilju; Son, Daryeon; Kim, In Yong; Song, Gwonhwa; Park, Gyuman; You, Seungkwon

doi:10.1016/j.ymben.2019.02.003

Cited by 27 publications

(27 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results revealed that overexpression of Sox2 markedly elevated the Gldc mRNA and protein levels, whereas Lin28A enhanced the protein but not the mRNA expression (Fig 2A). The protein level of Gldc was also mildly increased in Klf4 overexpressing MEFs (Fig 2A), which is consistent with Kang’s study (Kang et al, 2019). Furthermore, knockdown of Sox2 with shRNAs markedly decreased both the mRNA and protein levels of Gldc in V6.5 cells (Fig 2B), indicating that Sox2 is critical for the transcriptional activation of Gldc.…”

Section: Resultssupporting

confidence: 92%

“…More intriguingly, although cancer cells share a variety of properties with stem cells, it is much less understood how the GCS functions in PSCs than in other cells. Notably, during the submission of this manuscript, a very recent article described the role of the GCS in the maintenance and induction of pluripotency via metabolic regulation (Kang et al, 2019). However, additional mechanistic details, as well as the significance of this finding, remain to be further explored.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Glycine cleavage system determines the fate of pluripotent stem cells via the regulation of senescence and epigenetic modifications

et al. 2019

View full text Add to dashboard Cite

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 whereby GCS activation controls stem cell pluripotency by promoting H3K4me3 modification and preventing cellular senescence.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Glycine cleavage system determines the fate of pluripotent stem cells via the regulation of senescence and epigenetic modifications

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Indeed, L-threonine supplementation and induction of TDH supports induction of pluripotency through nuclear reprogramming by promoting H3K4me3 (Ryu and Han, 2011;Han et al, 2013;Chen and Wang, 2014). Recent evidence has also implicated GLDC, a key enzyme in the glycine cleavage, in early metabolic remodeling during nuclear reprogramming and maintenance of the pluripotent state (Kang et al, 2019). GLDC expression occurs early in the reprogramming process and appears to be downstream of the reprogramming factors KLF4 and c-MYC, and reprogramming efficiency can be impaired with GLDC knockdown and enhanced with GLDC overexpression.…”

Section: Energy Metabolism Drives Acquisition Of Pluripotency Throughmentioning

confidence: 99%

“…GLDC expression occurs early in the reprogramming process and appears to be downstream of the reprogramming factors KLF4 and c-MYC, and reprogramming efficiency can be impaired with GLDC knockdown and enhanced with GLDC overexpression. GLDC knockdown in mESCs leads to a reduction in a number of glycolytic intermediates and the loss of self-renewal, suggesting that GLDC functions in reprogramming by regulating glycolysis (Kang et al, 2019).…”

Section: Energy Metabolism Drives Acquisition Of Pluripotency Throughmentioning

confidence: 99%

Energy Metabolism Regulates Stem Cell Pluripotency

Tsogtbaatar

Landin

Minter-Dykhouse

et al. 2020

Front. Cell Dev. Biol.

173

138

View full text Add to dashboard Cite

Pluripotent stem cells (PSCs) are characterized by their unique capacity for both unlimited self-renewal and their potential to differentiate to all cell lineages contained within the three primary germ layers. While once considered a distinct cellular state, it is becoming clear that pluripotency is in fact a continuum of cellular states, all capable of self-renewal and differentiation, yet with distinct metabolic, mitochondrial and epigenetic features dependent on gestational stage. In this review we focus on two of the most clearly defined states: "naïve" and "primed" PSCs. Like other rapidly dividing cells, PSCs have a high demand for anabolic precursors necessary to replicate their genome, cytoplasm and organelles, while concurrently consuming energy in the form of ATP. This requirement for both anabolic and catabolic processes sufficient to supply a highly adapted cell cycle in the context of reduced oxygen availability, distinguishes PSCs from their differentiated progeny. During early embryogenesis PSCs adapt their substrate preference to match the bioenergetic requirements of each specific developmental stage. This is reflected in different mitochondrial morphologies, membrane potentials, electron transport chain (ETC) compositions, and utilization of glycolysis. Additionally, metabolites produced in PSCs can directly influence epigenetic and transcriptional programs, which in turn can affect self-renewal characteristics. Thus, our understanding of the role of metabolism in PSC fate has expanded from anabolism and catabolism to include governance of the pluripotent epigenetic landscape. Understanding the roles of metabolism and the factors influencing metabolic pathways in naïve and primed pluripotent states provide a platform for understanding the drivers of cell fate during development. This review highlights the roles of the major metabolic pathways in the acquisition and maintenance of the different states of pluripotency.

show abstract

“…GLDC is a regulator of glycolysis 39‐41 . It promotes glycolysis in non‐small cell lung carcinoma 41 and in pluripotent stem cells 39 .…”

Section: Discussionmentioning

confidence: 99%

Phosphatase of regenerating liver‐3 regulates cancer cell metabolism in multiple myeloma

et al. 2021

View full text Add to dashboard Cite

Cancer cells often depend on microenvironment signals from molecules such as cytokines for proliferation and metabolic adaptations. PRL‐3, a cytokine‐induced oncogenic phosphatase, is highly expressed in multiple myeloma cells and associated with poor outcome in this cancer. We studied whether PRL‐3 influences metabolism. Cells transduced to express PRL‐3 had higher aerobic glycolytic rate, oxidative phosphorylation, and ATP production than the control cells. PRL‐3 promoted glucose uptake and lactate excretion, enhanced the levels of proteins regulating glycolysis and enzymes in the serine/glycine synthesis pathway, a side branch of glycolysis. Moreover, mRNAs for these proteins correlated with PRL‐3 expression in primary patient myeloma cells. Glycine decarboxylase (GLDC) was the most significantly induced metabolism gene. Forced GLDC downregulation partly counteracted PRL‐3‐induced aerobic glycolysis, indicating GLDC involvement in a PRL‐3‐driven Warburg effect. AMPK, HIF‐1α, and c‐Myc, important metabolic regulators in cancer cells, were not mediators of PRL‐3’s metabolic effects. A phosphatase‐dead PRL‐3 mutant, C104S, promoted many of the metabolic changes induced by wild‐type PRL‐3, arguing that important metabolic effects of PRL‐3 are independent of its phosphatase activity. Through this study, PRL‐3 emerges as one of the key mediators of metabolic adaptations in multiple myeloma.

show abstract

Glycine decarboxylase regulates the maintenance and induction of pluripotency via metabolic control

Cited by 27 publications

References 40 publications

Glycine cleavage system determines the fate of pluripotent stem cells via the regulation of senescence and epigenetic modifications

Glycine cleavage system determines the fate of pluripotent stem cells via the regulation of senescence and epigenetic modifications

Energy Metabolism Regulates Stem Cell Pluripotency

Phosphatase of regenerating liver‐3 regulates cancer cell metabolism in multiple myeloma

Contact Info

Product

Resources

About