Metabolic Control over mTOR-Dependent Diapause-like State.,Developmental Cell

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Metabolic Control over mTOR-Dependent Diapause-like State.
Developmental Cell ( IF 10.7 ) Pub Date : 2020-01-27 , DOI: 10.1016/j.devcel.2019.12.018
Abdiasis M Hussein ₁ , Yuliang Wang ₂ , Julie Mathieu ₃ , Lilyana Margaretha ₄ , Chaozhong Song ₅ , Daniel C Jones ₆ , Christopher Cavanaugh ₇ , Jason W Miklas ₈ , Elisabeth Mahen ₅ , Megan R Showalter ₉ , Walter L Ruzzo ₁₀ , Oliver Fiehn ₉ , Carol B Ware ₇ , C Anthony Blau ₅ , Hannele Ruohola-Baker ₁₁

Affiliation

Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Molecular and Cellular Biology, University of Washington, Seattle, WA 98109, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Medicine, Division of Hematology, University of Washington, Seattle, WA 98195, USA.
Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA.
Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

Regulation of embryonic diapause, dormancy that interrupts the tight connection between developmental stage and time, is still poorly understood. Here, we characterize the transcriptional and metabolite profiles of mouse diapause embryos and identify unique gene expression and metabolic signatures with activated lipolysis, glycolysis, and metabolic pathways regulated by AMPK. Lipolysis is increased due to mTORC2 repression, increasing fatty acids to support cell survival. We further show that starvation in pre-implantation ICM-derived mouse ESCs induces a reversible dormant state, transcriptionally mimicking the in vivo diapause stage. During starvation, Lkb1, an upstream kinase of AMPK, represses mTOR, which induces a reversible glycolytic and epigenetically H4K16Ac-negative, diapause-like state. Diapause furthermore activates expression of glutamine transporters SLC38A1/2. We show by genetic and small molecule inhibitors that glutamine transporters are essential for the H4K16Ac-negative, diapause state. These data suggest that mTORC1/2 inhibition, regulated by amino acid levels, is causal for diapause metabolism and epigenetic state.

中文翻译：

对依赖mTOR的滞育样状态的代谢控制。

胚胎滞育的调节，休眠中断了发育阶段和时间之间的紧密联系，这一点仍然知之甚少。在这里，我们表征小鼠滞育性胚胎的转录和代谢产物特征，并通过激活的脂解，糖酵解和由AMPK调节的代谢途径来鉴定独特的基因表达和代谢特征。由于mTORC2抑制，脂解作用增加，脂肪酸增加以支持细胞存活。我们进一步表明，在植入前ICM衍生的小鼠胚胎干细胞中的饥饿诱导了可逆的休眠状态，转录模仿体内滞育阶段。在饥饿期间，AMPK的上游激酶Lkb1抑制mTOR，后者诱导可逆的糖酵解和表观遗传的H4K16Ac阴性，滞育性状态。滞育还激活谷氨酰胺转运蛋白SLC38A1 / 2的表达。我们通过遗传和小分子抑制剂表明，谷氨酰胺转运蛋白对于H4K16Ac阴性，滞育状态至关重要。这些数据表明，由氨基酸水平调节的mTORC1 / 2抑制是滞育代谢和表观遗传状态的原因。

更新日期：2020-01-27

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