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.
Cell Stem Cell. 2020 May 7;26(5):722-738.e7. doi: 10.1016/j.stem.2020.03.003. Epub 2020 Mar 30.
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.
可变聚腺苷酸化（APA）是一种通过控制 3' 非翻译区（3'-UTR）组成来调节 RNA 和蛋白质亚型表达的重要调控机制。APA 在干细胞层次结构中的相关性仍然难以捉摸。在这里，我们首先证明了 APA 调节剂 Pabpn1 对造血干细胞（HSC）功能的要求。然后，我们通过进行低输入 3' 测序并结合生物信息学管道来确定 HSC 和祖细胞的全基因组 APA 图谱（APAome）。这揭示了转录组范围内的动态 APA 模式以及在分化过程中以及在从静止到增殖的稳态或应激诱导转换期间 3'-UTR 的总体缩短。具体而言，我们表明 APA 通过 Nudt21 调节谷氨酸酶（Gls）同工型转换的激活诱导。通过增加 GAC:KGA 同工型比例来适应谷氨酰胺代谢，为 HSC 自我更新和适当的应激反应所需的多功能代谢途径提供燃料。我们的研究确立了 APA 作为协调 HSC 自我更新、行为和承诺的关键调控层。
