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通过α-酮戊二酸对多能性和生殖细胞命运进行代谢调控。

Metabolic regulation of pluripotency and germ cell fate through α-ketoglutarate.

机构信息

Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.

MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

出版信息

EMBO J. 2019 Jan 3;38(1). doi: 10.15252/embj.201899518. Epub 2018 Sep 26.

DOI:10.15252/embj.201899518
PMID:30257965
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6315289/
Abstract

An intricate link is becoming apparent between metabolism and cellular identities. Here, we explore the basis for such a link in an model for early mouse embryonic development: from naïve pluripotency to the specification of primordial germ cells (PGCs). Using single-cell RNA-seq with statistical modelling and modulation of energy metabolism, we demonstrate a functional role for oxidative mitochondrial metabolism in naïve pluripotency. We link mitochondrial tricarboxylic acid cycle activity to IDH2-mediated production of alpha-ketoglutarate and through it, the activity of key epigenetic regulators. Accordingly, this metabolite has a role in the maintenance of naïve pluripotency as well as in PGC differentiation, likely through preserving a particular histone methylation status underlying the transient state of developmental competence for the PGC fate. We reveal a link between energy metabolism and epigenetic control of cell state transitions during a developmental trajectory towards germ cell specification, and establish a paradigm for stabilizing fleeting cellular states through metabolic modulation.

摘要

代谢与细胞身份之间存在着复杂的联系。在这里，我们通过一种早期小鼠胚胎发育的模型来探讨这种联系的基础：从原始多能性到原始生殖细胞（PGC）的特化。我们使用单细胞 RNA-seq 结合统计建模和能量代谢的调节，证明了氧化线粒体代谢在原始多能性中的功能作用。我们将三羧酸循环活性与 IDH2 介导的α-酮戊二酸产生联系起来，并通过它与关键表观遗传调节剂的活性联系起来。因此，这种代谢物在维持原始多能性以及 PGC 分化中都发挥作用，可能是通过维持一种特定的组蛋白甲基化状态，这种状态是 PGC 命运的短暂发育能力的基础。我们揭示了在向生殖细胞特化的发育轨迹中，能量代谢和细胞状态转换的表观遗传控制之间的联系，并建立了通过代谢调节稳定短暂细胞状态的范例。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/b90a9c33c7b1/EMBJ-38-e99518-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/0b78b358e8ec/EMBJ-38-e99518-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/16a62a4a5103/EMBJ-38-e99518-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/aa75fef7ddc2/EMBJ-38-e99518-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/7aed34032d75/EMBJ-38-e99518-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/1401ace652c6/EMBJ-38-e99518-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/c74cd2b556eb/EMBJ-38-e99518-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/75e194b11232/EMBJ-38-e99518-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/fa468ae6a49b/EMBJ-38-e99518-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/18e7fbff0d1b/EMBJ-38-e99518-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/b90a9c33c7b1/EMBJ-38-e99518-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/0b78b358e8ec/EMBJ-38-e99518-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/16a62a4a5103/EMBJ-38-e99518-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/aa75fef7ddc2/EMBJ-38-e99518-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/7aed34032d75/EMBJ-38-e99518-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/1401ace652c6/EMBJ-38-e99518-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/c74cd2b556eb/EMBJ-38-e99518-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/75e194b11232/EMBJ-38-e99518-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/fa468ae6a49b/EMBJ-38-e99518-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/18e7fbff0d1b/EMBJ-38-e99518-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/842d/6315289/b90a9c33c7b1/EMBJ-38-e99518-g011.jpg

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