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

Shengya Tian,Ronghui Yan,Huafeng Zhang,Lihua Wang,Yang Cao,Xiuying Zhong,Shengqi Shen,Junru Feng,Yongping Cai,Dongdong Yang,Ping Gao

doi:10.26508/lsa.201900413

Abstract

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.

Highlights

Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells, have the ability to selfrenew indefinitely and to differentiate into almost any type of somatic cell (Takahashi & Yamanaka, 2006; Ying et al, 2008; Shi et al, 2017)
Knockdown of glycine decarboxylase (Gldc) in V6.5 cells significantly decreased the activity of the glycine cleavage system (GCS) (Fig 1K), suggesting that the induced Gldc expression is responsible for the activation of the GCS in mouse embryonic stem cells (mESCs) and induced pluripotent stem cells (iPSCs). These data demonstrate that the Gldc-mediated GCS is activated in PSCs and during somatic cell reprogramming
Consistent with previous reports (Wang et al, 2009; Shyh-Chang et al, 2013), our data showed that threonine dehydrogenase (Tdh), the enzyme that catalyses threonine oxidation, was up-regulated in iPSCs and mESCs (Figs 1C and S1A)

Summary

Introduction

Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have the ability to selfrenew indefinitely and to differentiate into almost any type of somatic cell (Takahashi & Yamanaka, 2006; Ying et al, 2008; Shi et al, 2017). Mouse ESCs have the ability to catabolize threonine by activating threonine dehydrogenase (Tdh) to maintain an advantageous metabolic state; mouse ESCs are very sensitive to threonine restriction (Wang et al, 2009; Shyh-Chang et al, 2013). An elegant study by Zhang et al (2016) showed that LIN28A regulated the serine synthesis pathway (SSP) in PSCs (Zhang et al, 2016). Despite these important findings regarding amino acid metabolism in PSCs, the underlying mechanisms and significance of amino acid metabolism in stem cells remain to be further explored

Methods

Results

Conclusion