Metabolic Remodelling During Early Mouse Embryo Development

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2021 Oct 15

PMID 34650276

Citations 41

Authors

Jing Zhao

Ke Yao

Hua Yu

Ling Zhang

Yuyan Xu

Lang Chen

Zhen Sun

Yuqing Zhu

Cheng Zhang

Yuli Qian

Shuyan Ji

Hongru Pan

Min Zhang

Jie Chen

Cristina Correia

Taylor Weiskittel

Da-Wei Lin

Yuzheng Zhao

Sriram Chandrasekaran

Xudong Fu

Dan Zhang

Heng-Yu Fan

Wei Xie

Hu Li

Zeping Hu

Jin Zhang

Affiliations

Soon will be listed here.

Abstract

During early mammalian embryogenesis, changes in cell growth and proliferation depend on strict genetic and metabolic instructions. However, our understanding of metabolic reprogramming and its influence on epigenetic regulation in early embryo development remains elusive. Here we show a comprehensive metabolomics profiling of key stages in mouse early development and the two-cell and blastocyst embryos, and we reconstructed the metabolic landscape through the transition from totipotency to pluripotency. Our integrated metabolomics and transcriptomics analysis shows that while two-cell embryos favour methionine, polyamine and glutathione metabolism and stay in a more reductive state, blastocyst embryos have higher metabolites related to the mitochondrial tricarboxylic acid cycle, and present a more oxidative state. Moreover, we identify a reciprocal relationship between α-ketoglutarate (α-KG) and the competitive inhibitor of α-KG-dependent dioxygenases, L-2-hydroxyglutarate (L-2-HG), where two-cell embryos inherited from oocytes and one-cell zygotes display higher L-2-HG, whereas blastocysts show higher α-KG. Lastly, increasing 2-HG availability impedes erasure of global histone methylation markers after fertilization. Together, our data demonstrate dynamic and interconnected metabolic, transcriptional and epigenetic network remodelling during early mouse embryo development.

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References

Zhang J, Zhao J, Dahan P, Lu V, Zhang C, Li H . Metabolism in Pluripotent Stem Cells and Early Mammalian Development. Cell Metab. 2018; 27(2):332-338. DOI: 10.1016/j.cmet.2018.01.008. View

Chronopoulou E, Harper J . IVF culture media: past, present and future. Hum Reprod Update. 2014; 21(1):39-55. DOI: 10.1093/humupd/dmu040. View

Conaghan J, Handyside A, Winston R, Leese H . Effects of pyruvate and glucose on the development of human preimplantation embryos in vitro. J Reprod Fertil. 1993; 99(1):87-95. DOI: 10.1530/jrf.0.0990087. View

Brinster R . STUDIES ON THE DEVELOPMENT OF MOUSE EMBRYOS IN VITRO. II. THE EFFECT OF ENERGY SOURCE. J Exp Zool. 1965; 158:59-68. PMC: 4943454. DOI: 10.1002/jez.1401580106. View

Brown J, WHITTINGHAM D . The roles of pyruvate, lactate and glucose during preimplantation development of embryos from F1 hybrid mice in vitro. Development. 1991; 112(1):99-105. DOI: 10.1242/dev.112.1.99. View

Gardner D . Changes in requirements and utilization of nutrients during mammalian preimplantation embryo development and their significance in embryo culture. Theriogenology. 2000; 49(1):83-102. DOI: 10.1016/s0093-691x(97)00404-4. View

Gardner D, Lane M . Culture and selection of viable blastocysts: a feasible proposition for human IVF?. Hum Reprod Update. 1997; 3(4):367-82. DOI: 10.1093/humupd/3.4.367. View

Houghton F, Thompson J, Kennedy C, Leese H . Oxygen consumption and energy metabolism of the early mouse embryo. Mol Reprod Dev. 1996; 44(4):476-85. DOI: 10.1002/(SICI)1098-2795(199608)44:4<476::AID-MRD7>3.0.CO;2-I. View

Leese H . Metabolism of the preimplantation embryo: 40 years on. Reproduction. 2012; 143(4):417-27. DOI: 10.1530/REP-11-0484. View

10.

Xue Z, Huang K, Cai C, Cai L, Jiang C, Feng Y . Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing. Nature. 2013; 500(7464):593-7. PMC: 4950944. DOI: 10.1038/nature12364. View

11.

Wu J, Huang B, Chen H, Yin Q, Liu Y, Xiang Y . The landscape of accessible chromatin in mammalian preimplantation embryos. Nature. 2016; 534(7609):652-7. DOI: 10.1038/nature18606. View

12.

Lu F, Liu Y, Inoue A, Suzuki T, Zhao K, Zhang Y . Establishing Chromatin Regulatory Landscape during Mouse Preimplantation Development. Cell. 2016; 165(6):1375-1388. PMC: 6625655. DOI: 10.1016/j.cell.2016.05.050. View

13.

Dahl J, Jung I, Aanes H, Greggains G, Manaf A, Lerdrup M . Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition. Nature. 2016; 537(7621):548-552. PMC: 6283663. DOI: 10.1038/nature19360. View

14.

Zhang B, Zheng H, Huang B, Li W, Xiang Y, Peng X . Allelic reprogramming of the histone modification H3K4me3 in early mammalian development. Nature. 2016; 537(7621):553-557. DOI: 10.1038/nature19361. View

15.

Wang C, Liu X, Gao Y, Yang L, Li C, Liu W . Reprogramming of H3K9me3-dependent heterochromatin during mammalian embryo development. Nat Cell Biol. 2018; 20(5):620-631. DOI: 10.1038/s41556-018-0093-4. View

16.

Macfarlan T, Gifford W, Driscoll S, Lettieri K, Rowe H, Bonanomi D . Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature. 2012; 487(7405):57-63. PMC: 3395470. DOI: 10.1038/nature11244. View

17.

Nichols J, Smith A . Naive and primed pluripotent states. Cell Stem Cell. 2009; 4(6):487-92. DOI: 10.1016/j.stem.2009.05.015. View

18.

Smith A . Formative pluripotency: the executive phase in a developmental continuum. Development. 2017; 144(3):365-373. PMC: 5430734. DOI: 10.1242/dev.142679. View

19.

TeSlaa T, Teitell M . Pluripotent stem cell energy metabolism: an update. EMBO J. 2014; 34(2):138-53. PMC: 4337063. DOI: 10.15252/embj.201490446. View

20.

Zhou W, Choi M, Margineantu D, Margaretha L, Hesson J, Cavanaugh C . HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition. EMBO J. 2012; 31(9):2103-16. PMC: 3343469. DOI: 10.1038/emboj.2012.71. View