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Mapping active gene-regulatory regions in human repopulating long-term HSCs

Summary Genes that regulate hematopoietic stem cell (HSC) self-renewal, proliferation, and differentiation are tightly controlled by regulatory regions. However, mapping such regions relies on surface markers and immunophenotypic definition of HSCs. Here, we use γ-retroviral integration sites (γRV I...

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Main Authors: Wünsche, Peer (Author) , Eckert, Elias Simon Peter (Author) , Fronza, Raffaele (Author) , Gil-Fariña, Irene (Author) , Schmidt, Manfred (Author) , Kalle, Christof von (Author) , Herbst, Friederike (Author) , Glimm, Hanno (Author)
Format: Article (Journal)
Language:English
Published: 5 July 2018
In: Cell stem cell
Year: 2018, Volume: 23, Issue: 1, Pages: 132-146
ISSN:1875-9777
DOI:10.1016/j.stem.2018.06.003
Online Access:Verlag, Volltext: http://dx.doi.org/10.1016/j.stem.2018.06.003
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S1934590918302856
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Author Notes:Peer Wünsche, Elias S.P. Eckert, Tim Holland-Letz, Anna Paruzynski, Agnes Hotz-Wagenblatt, Raffaele Fronza, Tim Rath, Irene Gil-Farina, Manfred Schmidt, Christof von Kalle, Christoph Klein, Claudia R. Ball, Friederike Herbst, Hanno Glimm
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Summary:Summary Genes that regulate hematopoietic stem cell (HSC) self-renewal, proliferation, and differentiation are tightly controlled by regulatory regions. However, mapping such regions relies on surface markers and immunophenotypic definition of HSCs. Here, we use γ-retroviral integration sites (γRV ISs) from a gene therapy trial for 10 patients with Wiskott-Aldrich syndrome to mark active enhancers and promoters in functionally defined long-term repopulating HSCs. Integration site clusters showed the highest ATAC-seq signals at HSC-specific peaks and strongly correlated with hematopoietic risk variants. Tagged genes were significantly enriched for HSC gene sets. We were able to map over 3,000 HSC regulatory regions in late-contributing HSCs, and we used these data to identify miR-10a and miR-335 as two miRNAs regulating early hematopoiesis. In this study, we show that viral insertion sites can be used as molecular tags to assess chromatin conformation on functionally defined cell populations, thereby providing a genome-wide resource for regulatory regions in human repopulating long-term HSCs.
Item Description:Gesehen am 11.07.2018
Physical Description:Online Resource
ISSN:1875-9777
DOI:10.1016/j.stem.2018.06.003

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