• ISSN 1674-8301
  • CN 32-1810/R
Volume 35 Issue 1
Jan.  2021
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Article Contents
Xing Ming, Wang Na, Zeng Hanyi, Zhang Jun. α-ketoglutarate promotes the specialization of primordial germ cell-like cells through regulating epigenetic reprogramming[J]. The Journal of Biomedical Research, 2021, 35(1): 36-46. doi: 10.7555/JBR.34.20190160
Citation: Xing Ming, Wang Na, Zeng Hanyi, Zhang Jun. α-ketoglutarate promotes the specialization of primordial germ cell-like cells through regulating epigenetic reprogramming[J]. The Journal of Biomedical Research, 2021, 35(1): 36-46. doi: 10.7555/JBR.34.20190160

α-ketoglutarate promotes the specialization of primordial germ cell-like cells through regulating epigenetic reprogramming

doi: 10.7555/JBR.34.20190160
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  • Corresponding author: Jun Zhang, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China. Tel: +86-25-86869381, E-mail: zhang_jun@njmu.edu.cn
  • Received: 2019-12-26
  • Revised: 2020-05-20
  • Accepted: 2020-06-05
  • Published: 2020-08-06
  • Issue Date: 2021-01-28
  • There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression. However, the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely unknown. Here, we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells (EpiLCs) and primordial germ cell-like cells (PGCLCs). More importantly, we found that inhibition of glutaminolysis by bis-2- (5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) impeded PGCLC specialization, but the impediment could be rescued by addition of α-ketoglutarate (αKG), the intermediate metabolite of oxidative phosphorylation and glutaminolysis. Moreover, adding αKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3K27me3 demethylation. Thus, our study reveals the importance of metabolite αKG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.


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  • [1]
    Saitou M, Yamaji M. Primordial germ cells in mice[J]. Cold Spring Harb Perspect Biol,2012, 4(11): a008375.
    Ohinata Y, Payer B, O'Carroll D, et al. Blimp1 is a critical determinant of the germ cell lineage in mice[J]. Nature,2005, 436(7048): 207–213. doi: 10.1038/nature03813
    Yamaji M, Seki Y, Kurimoto K, et al. Critical function of Prdm14 for the establishment of the germ cell lineage in mice[J]. Nat Genet,2008, 40(8): 1016–1022. doi: 10.1038/ng.186
    Schäfer S, Anschlag J, Nettersheim D, et al. The role of BLIMP1 and its putative downstream target TFAP2C in germ cell development and germ cell tumours[J]. Int J Androl,2011, 34(4pt2): e152–e159. doi: 10.1111/j.1365-2605.2011.01167.x
    Aramaki S, Hayashi K, Kurimoto K, et al. A Mesodermal Factor, T, Specifies mouse germ cell fate by directly activating germline determinants[J]. Dev Cell,2013, 27(5): 516–529. doi: 10.1016/j.devcel.2013.11.001
    De Miguel MP, Cheng LZ, Holland EC, et al. Dissection of the c-Kit signaling pathway in mouse primordial germ cells by retroviral-mediated gene transfer[J].Proc Natl Acad Sci USA,2002, 99(16): 10458–10463. doi: 10.1073/pnas.122249399
    Saitou M, Kagiwada S, Kurimoto K. Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells[J]. Development,2012, 139(1): 15–31. doi: 10.1242/dev.050849
    Hayashi K, Ohta H, Kurimoto K, et al. Reconstitution of the Mouse Germ Cell specification pathway in culture by pluripotent stem cells[J]. Cell,2011, 146(4): 519–532. doi: 10.1016/j.cell.2011.06.052
    Hayashi K, Saitou M. Generation of eggs from mouse embryonic stem cells and induced pluripotent stem cells[J]. Nat Protoc,2013, 8(8): 1513–1524. doi: 10.1038/nprot.2013.090
    Saitou M, Miyauchi H. Gametogenesis from pluripotent stem cells[J]. Cell Stem Cell,2016, 18(6): 721–735. doi: 10.1016/j.stem.2016.05.001
    Zhou Q, Wang M, Yuan Y, et al. Complete meiosis from embryonic stem cell-derived germ cells in vitro[J]. Cell Stem Cell,2016, 18(3): 330–340. doi: 10.1016/j.stem.2016.01.017
    Kurimoto K, Yabuta Y, Hayashi K, et al. Quantitative dynamics of chromatin remodeling during germ cell specification from mouse embryonic stem cells[J]. Cell Stem Cell,2015, 16(5): 517–532. doi: 10.1016/j.stem.2015.03.002
    Sharma U, Rando OJ. Metabolic inputs into the epigenome[J]. Cell Metab,2017, 25(3): 544–558. doi: 10.1016/j.cmet.2017.02.003
    Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy[J]. Nat Rev Cancer,2016, 16(10): 619–634. doi: 10.1038/nrc.2016.71
    Klysz D, Tai XG, Robert PA, et al. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation[J]. Sci Signal,2015, 8(396): ra97. doi: 10.1126/scisignal.aab2610
    Yang QY, Liang XW, Sun XF, et al. AMPK/α-Ketoglutarate axis dynamically mediates DNA Demethylation in the Prdm16 promoter and brown Adipogenesis[J]. Cell Metab,2016, 24(4): 542–554. doi: 10.1016/j.cmet.2016.08.010
    Carey BW, Finley LWS, Cross JR, et al. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells[J]. Nature,2015, 518(7539): 413–416. doi: 10.1038/nature13981
    Park S, Safi R, Liu XJ, et al. Inhibition of ERRα prevents mitochondrial pyruvate uptake exposing NADPH-generating pathways as targetable vulnerabilities in breast cancer[J]. Cell Rep,2019, 27(12): 3587–3601. doi: 10.1016/j.celrep.2019.05.066
    TeSlaa T, Chaikovsky AC, Lipchina I, et al. α-Ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells[J]. Cell Metab,2016, 24(3): 485–493. doi: 10.1016/j.cmet.2016.07.002
    Hofstetter C, Kampka JM, Huppertz S, et al. Inhibition of KDM6 activity during murine ESC differentiation induces DNA Damage[J]. J Cell Sci,2016, 129(4): 788–803. doi: 10.1242/jcs.175174
    Qiu YP, Cai GX, SU MM, et al. Serum metabolite profiling of human colorectal cancer using GC-TOFMS and UPLC-QTOFMS[J]. J Proteome Res,2009, 8(10): 4844–4850. doi: 10.1021/pr9004162
    Zielke HR, Zielke CL, Ozand PT. Glutamine: a major energy source for cultured mammalian cells[J]. Fed Proc,1984, 43(1): 121–125.
    Song M, Kim SH, Im CY, et al. Recent development of small molecule glutaminase inhibitors[J]. Curr Top Med Chem,2018, 18(6): 432–443. doi: 10.2174/1568026618666180525100830
    Agger K, Cloos PAC, Christensen J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development[J]. Nature,2007, 449(7163): 731–734. doi: 10.1038/nature06145
    Yan NN, Xu L, Wu XB, et al. GSKJ4, an H3K27me3 demethylase inhibitor, effectively suppresses the breast cancer stem cells[J]. Exp Cell Res,2017, 359(2): 405–414. doi: 10.1016/j.yexcr.2017.08.024
    Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial Reactive Oxygen Species (ROS) and ROS-induced ROS release[J]. Physiol Rev,2014, 94(3): 909–950. doi: 10.1152/physrev.00026.2013
    Zha ZM, Wang JH, Li SL, et al. Pitavastatin attenuates AGEs-induced mitophagy via inhibition of ROS generation in the mitochondria of cardiomyocytes[J]. J Biomed Res,2018, 32(4): 281–287.
    Guo Z, Zhou BR, Li W, et al. Hydrogen-rich saline protects against ultraviolet B radiation injury in rats[J]. J Biomed Res,2012, 26(5): 365–371. doi: 10.7555/JBR.26.20110037
    Zhang R, Kang KA, Kim KC, et al. Oxidative stress causes epigenetic alteration of CDX1 expression in colorectal cancer cells[J]. Gene,2013, 524(2): 214–219. doi: 10.1016/j.gene.2013.04.024
    Periyasamy K, Sivabalan V, Baskaran K, et al. Cellular metabolic energy modulation by tangeretin in 7,12-dimethylbenz(a) anthracene-induced breast cancer[J]. J Biomed Res,2016, 30(2): 134–141.
    Etchegaray JP, Mostoslavsky R. Interplay between metabolism and epigenetics: A nuclear adaptation to environmental changes[J]. Mol Cell,2016, 62(5): 695–711. doi: 10.1016/j.molcel.2016.05.029
    Chisolm DA, Weinmann AS. Connections between metabolism and epigenetics in programming cellular differentiation[J]. Annu Rev Immunol,2018, 36: 221–246. doi: 10.1146/annurev-immunol-042617-053127
    Mentch SJ, Locasale JW. One-carbon metabolism and epigenetics: understanding the specificity[J]. Ann N Y Acad Sci,2016, 1363(1): 91–98. doi: 10.1111/nyas.12956
    Sivanand S, Viney I, Wellen KE. Spatiotemporal control of acetyl-CoA metabolism in chromatin regulation[J]. Trends Biochem Sci,2018, 43(1): 61–74. doi: 10.1016/j.tibs.2017.11.004
    Hwang IY, Kwak S, Lee S, et al. Psat1-dependent fluctuations in α-ketoglutarate affect the timing of ESC differentiation[J]. Cell Metab,2016, 24(3): 494–501. doi: 10.1016/j.cmet.2016.06.014
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