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Cell Stem Cell. 2018 Jul 5;23(1):132-146.e9. doi: 10.1016/j.stem.2018.06.003.

Mapping Active Gene-Regulatory Regions in Human Repopulating Long-Term HSCs.

Author information

1
Department of Translational and Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
2
Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
BioNTech RNA Pharmaceuticals, Mainz, Germany.
4
Core Facility Omics IT and Data Management, German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; GeneWerk GmbH, Heidelberg, Germany.
7
Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany.
8
Department of Translational Medical Oncology, NCT-Dresden, University Hospital, Carl Gustav Carus, Technische Universität Dresden, Dresden and DKFZ, Heidelberg, Germany.
9
Department of Translational and Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
Department of Translational and Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Translational Medical Oncology, NCT-Dresden, University Hospital, Carl Gustav Carus, Technische Universität Dresden, Dresden and DKFZ, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: hanno.glimm@nct-dresden.de.

Abstract

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.

KEYWORDS:

HSC; enhancer; hematopoietic stem cell; human; miRNA-10a; miRNA-335; non-coding regulatory regions; viral insertion sites

Comment in

PMID:
29979988
DOI:
10.1016/j.stem.2018.06.003
[Indexed for MEDLINE]
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