Differential Alternative Polyadenylation Landscapes Mediate Hematopoietic Stem Cell Activation and Regulate Glutamine Metabolism.,Cell Stem Cell

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Differential Alternative Polyadenylation Landscapes Mediate Hematopoietic Stem Cell Activation and Regulate Glutamine Metabolism.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-03-30 , DOI: 10.1016/j.stem.2020.03.003
Pia Sommerkamp ₁ , Sandro Altamura ₂ , Simon Renders ₃ , Andreas Narr ₁ , Luisa Ladel ₄ , Petra Zeisberger ₄ , Paula Leonie Eiben ₄ , Malak Fawaz ₅ , Michael A Rieger ₆ , Nina Cabezas-Wallscheid ₇ , Andreas Trumpp ₈

Affiliation

Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69117 Heidelberg, Germany.
Department of Pediatric Hematology, Oncology and Immunology, Heidelberg University Medical Center, 69120 Heidelberg, Germany.
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, 69120 Heidelberg, Germany.
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.
LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany.
LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Frankfurt Cancer Institute, 60596 Frankfurt, Germany.
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.

Alternative polyadenylation (APA) is emerging as an important regulatory mechanism of RNA and protein isoform expression by controlling 3' untranslated region (3'-UTR) composition. The relevance of APA in stem cell hierarchies remains elusive. Here, we first demonstrate the requirement of the APA regulator Pabpn1 for hematopoietic stem cell (HSC) function. We then determine the genome-wide APA landscape (APAome) of HSCs and progenitors by performing low-input 3' sequencing paired with bioinformatic pipelines. This reveals transcriptome-wide dynamic APA patterns and an overall shortening of 3'-UTRs during differentiation and upon homeostatic or stress-induced transition from quiescence to proliferation. Specifically, we show that APA regulates activation-induced Glutaminase (Gls) isoform switching by Nudt21. This adaptation of the glutamine metabolism by increasing the GAC:KGA isoform ratio fuels versatile metabolic pathways necessary for HSC self-renewal and proper stress response. Our study establishes APA as a critical regulatory layer orchestrating HSC self-renewal, behavior, and commitment.

中文翻译：

差异化替代多腺苷酸化景观介导造血干细胞活化并调节谷氨酰胺代谢。

通过控制 3' 非翻译区 (3'-UTR) 组成，替代多腺苷酸化 (APA) 正在成为 RNA 和蛋白质异构体表达的重要调节机制。APA 在干细胞层次结构中的相关性仍然难以捉摸。在这里，我们首先展示了 APA 调节器 Pabpn1 对造血干细胞 (HSC) 功能的要求。然后，我们通过执行与生物信息学管道配对的低输入 3' 测序来确定 HSC 和祖细胞的全基因组 APA 景观 (APAome)。这揭示了转录组范围内的动态 APA 模式和 3'-UTR 在分化过程中以及在稳态或压力诱导的从静止到增殖的转变时的整体缩短。具体来说，我们表明 APA 调节 Nudt21 激活诱导的谷氨酰胺酶 (Gls) 异构体转换。这种通过增加 GAC:KGA 异构体比率来适应谷氨酰胺代谢，为 HSC 自我更新和适当的应激反应所必需的多种代谢途径提供了燃料。我们的研究将 APA 确立为协调 HSC 自我更新、行为和承诺的关键监管层。

更新日期：2020-03-30

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