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SETD1A protects HSCs from activation-induced functional decline in vivo.

Authors
  • Arndt, Kathrin1
  • Kranz, Andrea2
  • Fohgrub, Juliane1
  • Jolly, Adrien3
  • Bledau, Anita S2
  • Di Virgilio, Michela4
  • Lesche, Mathias5
  • Dahl, Andreas5
  • Höfer, Thomas3
  • Stewart, A Francis2
  • Waskow, Claudia1, 6, 7, 8
  • 1 Regeneration in Hematopoiesis, Institute for Immunology, and.
  • 2 Genomics, Biotechnology Center, Center for Molecular and Cellular Bioengineering, Technische Universität (TU) Dresden, Dresden, Germany. , (Germany)
  • 3 Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany. , (Germany)
  • 4 Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. , (Germany)
  • 5 Deep Sequencing Group SFB655, Biotechnology Center, and.
  • 6 Department of Medicine III, Faculty of Medicine, TU Dresden, Dresden, Germany. , (Germany)
  • 7 Regeneration in Hematopoiesis, Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany; and. , (Germany)
  • 8 Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany. , (Germany)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Mar 22, 2018
Volume
131
Issue
12
Pages
1311–1324
Identifiers
DOI: 10.1182/blood-2017-09-806844
PMID: 29348130
Source
Medline
Language
English
License
Unknown

Abstract

The regenerative capacity of hematopoietic stem cells (HSCs) is limited by the accumulation of DNA damage. Conditional mutagenesis of the histone 3 lysine 4 (H3K4) methyltransferase, Setd1a, revealed that it is required for the expression of DNA damage recognition and repair pathways in HSCs. Specific deletion of Setd1a in adult long-term (LT) HSCs is compatible with adult life and has little effect on the maintenance of phenotypic LT-HSCs in the bone marrow. However, SETD1A-deficient LT-HSCs lose their transcriptional cellular identity, accompanied by loss of their proliferative capacity and stem cell function under replicative stress in situ and after transplantation. In response to inflammatory stimulation, SETD1A protects HSCs and progenitors from activation-induced attrition in vivo. The comprehensive regulation of DNA damage responses by SETD1A in HSCs is clearly distinct from the key roles played by other epigenetic regulators, including the major leukemogenic H3K4 methyltransferase MLL1, or MLL5, indicating that HSC identity and function is supported by cooperative specificities within an epigenetic framework. © 2018 by The American Society of Hematology.

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