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Differential alternative polyadenylation landscapes mediate hematopoietic stem cell activation and regulate glutamine metabolism

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 re...

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Main Authors: Sommerkamp, Pia (Author) , Altamura, Sandro (Author) , Renders, Simon (Author) , Narr, Andreas (Author) , Ladel, Luisa (Author) , Zeisberger, Petra (Author) , Eiben, Paula Leonie (Author) , Fawaz, Malak (Author) , Rieger, Michael A. (Author) , Cabezas-Wallscheid, Nina (Author) , Trumpp, Andreas (Author)
Format: Article (Journal)
Language:English
Published: March 30, 2020
In: Cell stem cell
Year: 2020, Volume: 26, Issue: 5, Pages: 722-738.e7
ISSN:1875-9777
DOI:10.1016/j.stem.2020.03.003
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.stem.2020.03.003
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S1934590920300953
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Author Notes: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
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Summary: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.
Item Description:Gesehen am 06.04.2020
Physical Description:Online Resource
ISSN:1875-9777
DOI:10.1016/j.stem.2020.03.003

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