德国海德堡干细胞技术与实验医学研究所Andreas Trumpp和Nina Cabezas-Wallscheid研究组合作取得一项新成果。他们发现差异化的可替代性聚腺苷酸化（APA）全览介导造血干细胞（HSC）活化并调节谷氨酰胺代谢。2020年3月30日出版的《细胞-干细胞》杂志发表了这项成果。

他们首先证明HSC发挥功能需要APA调控子Pabpn1参与。然后，他们通过实行低输入3'测序与生物信息流水线配对，确定HSC和祖细胞的全基因组APA全览（APAome）。这揭示了在转录组范围内的动态APA模式和分化过程中，以及在稳态或应激诱导的从静止到增殖的转换过程中，3'非翻译区（3'-UTR）的整体缩短。

具体来说，他们表明APA通过Nudt21调节激活诱导的谷氨酰胺酶（Gls）异构体转换。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提供了多种多样的代谢途径。他们的研究将APA建立为协调HSC自我更新、行为和承诺的关键调控层级。

据悉，通过控制3'-UTR的组成，APA正在成为RNA和蛋白质同工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确定。

附：英文原文

Title: Differential Alternative Polyadenylation Landscapes Mediate Hematopoietic Stem Cell Activation and Regulate Glutamine Metabolism

Author: Pia Sommerkamp, Sandro Altamura, Simon Renders, Andreas Narr, Luisa Ladel, Petra Zeisberger, Paula Leonie Eiben, Malak Fawaz, Michael A. Rieger, Nina Cabezas-Wallscheid, Andreas Trumpp

Issue&Volume: 2020-03-30

Abstract: Alternative polyadenylation (APA) is emerging as an important regulatory mechanismof 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 APAlandscape (APAome) of HSCs and progenitors by performing low-input 3′ sequencing pairedwith bioinformatic pipelines. This reveals transcriptome-wide dynamic APA patternsand an overall shortening of 3′-UTRs during differentiation and upon homeostatic orstress-induced transition from quiescence to proliferation. Specifically, we showthat APA regulates activation-induced Glutaminase (Gls) isoform switching by Nudt21. This adaptation of the glutamine metabolism by increasing the GAC:KGA isoform ratiofuels versatile metabolic pathways necessary for HSC self-renewal and proper stressresponse. Our study establishes APA as a critical regulatory layer orchestrating HSCself-renewal, behavior, and commitment.

DOI: 10.1016/j.stem.2020.03.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30095-3