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

Sommerkamp, P., Altamura, S., Renders, S., Narr, A., Ladel, L., Zeisberger, P., et al. (2020). Differential Alternative Polyadenylation Landscapes Mediate Hematopoietic Stem Cell Activation and Regulate Glutamine Metabolism. Cell Stem Cell, 26, 722-738. doi:10.1016/j.stem.2020.03.003.

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Sommerkamp et al..pdf (Publisher version), 3MB
 
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2020
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 Creators:
Sommerkamp, Pia1, Author
Altamura, Sandro1, Author
Renders, Simon1, Author
Narr, Andreas1, Author
Ladel, Luisa1, Author
Zeisberger, Petra1, Author
Eiben, Paula Leonie1, Author
Fawaz, Malak1, Author
Rieger, Michael A.1, Author
Cabezas-Wallscheid, Nina2, Author              
Trumpp, Andreas1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, ou_2243641              

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Free keywords: alternative polyadenylation; APAome; 3′-seq; hematopoietic stem cell; inflammation; glutaminolysis; Pabpn1; Nudt21; GAC; KGA
 Abstract: 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.

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Language(s): eng - English
 Dates: 2020-03-30
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.stem.2020.03.003
 Degree: -

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Title: Cell Stem Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 26 Sequence Number: - Start / End Page: 722 - 738 Identifier: ISSN: 1934-5909
CoNE: https://pure.mpg.de/cone/journals/resource/1934-5909