1. Stem Cells and Regenerative Medicine
Download icon

The H3K4 methyltransferase Setd1b is essential for hematopoietic stem and progenitor cell homeostasis in mice

  1. Kerstin Schmidt
  2. Qinyu Zhang
  3. Alpaslan Tasdogan
  4. Andreas Petzold
  5. Andreas Dahl
  6. Borros M Arneth
  7. Robert Slany
  8. Hans Jörg Fehling
  9. Andrea Kranz  Is a corresponding author
  10. Adrian Francis Stewart  Is a corresponding author
  11. Konstantinos Anastassiadis  Is a corresponding author
  1. Technische Universität Dresden, Germany
  2. University Hospital Ulm, Germany
  3. Hospital of the Universities Giessen and Marburg, Germany
  4. Friedrich Alexander Universität Erlangen, Germany
Research Article
  • Cited 14
  • Views 2,304
  • Annotations
Cite this article as: eLife 2018;7:e27157 doi: 10.7554/eLife.27157

Abstract

Hematopoietic stem cells require MLL1, which is one of six Set1/Trithorax-type histone 3 lysine 4 (H3K4) methyltransferases in mammals and clinically the most important leukemia gene. Here we add to emerging evidence that all six H3K4 methyltransferases play essential roles in the hematopoietic system by showing that conditional mutagenesis of Setd1b in adult mice provoked aberrant homeostasis of hematopoietic stem and progenitor cells (HSPCs). Using both ubiquitous and hematopoietic-specific deletion strategies the loss of Setd1b resulted in peripheral thrombo- and lymphocytopenia, multilineage dysplasia, myeloid-biased extramedullary hematopoiesis in the spleen, and lethality. By transplantation experiments and expression profiling we determined that Setd1b is autonomously required in the hematopoietic lineages where it regulates key lineage specification components, including Cebpa, Gata1, and Klf1. Altogether, these data imply that the Set1/Trithorax-type epigenetic machinery sustains different aspects of hematopoiesis and constitutes a second framework additional to the transcription factor hierarchy of hematopoietic homeostasis.

Data availability

Sequencing data have been deposited in GEO under accession code GSE97976

The following data sets were generated

Article and author information

Author details

  1. Kerstin Schmidt

    Stem Cell Engineering, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9596-4026
  2. Qinyu Zhang

    Genomics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Alpaslan Tasdogan

    Institute of Immunology, University Hospital Ulm, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Andreas Petzold

    Deep Sequencing Group, DFG - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Andreas Dahl

    Deep Sequencing Group, DFG - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Borros M Arneth

    Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Hospital of the Universities Giessen and Marburg, Giessen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Robert Slany

    Department of Genetics, Friedrich Alexander Universität Erlangen, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Hans Jörg Fehling

    Institute of Immunology, University Hospital Ulm, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Andrea Kranz

    Genomics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
    For correspondence
    andrea.kranz@biotec.tu-dresden.de
    Competing interests
    The authors declare that no competing interests exist.
  10. Adrian Francis Stewart

    Genomics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
    For correspondence
    francis.stewart@tu-dresden.de
    Competing interests
    The authors declare that no competing interests exist.
  11. Konstantinos Anastassiadis

    Stem Cell Engineering, Biotechnology Center, Technische Universität Dresden, Dresden, Germany
    For correspondence
    konstantinos.anastassiadis@tu-dresden.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9814-0559

Funding

Deutsche Forschungsgemeinschaft (SPP1463/2 KR2154/4-1)

  • Andrea Kranz

Else Kröner-Fresenius-Stiftung (Stipend to Alpaslan Tasdogan)

  • Alpaslan Tasdogan

Deutsche Forschungsgemeinschaft (SPP1463 SL27/7-2)

  • Robert Slany

Deutsche Forschungsgemeinschaft (SFB1074 project A2)

  • Hans Jörg Fehling

Deutsche Forschungsgemeinschaft (SPP1463/2 STE903/5-1)

  • Adrian Francis Stewart

Deutsche Forschungsgemeinschaft (SFB655 project B1)

  • Konstantinos Anastassiadis

Deutsche Forschungsgemeinschaft (SFB655)

  • Andreas Dahl

Dresden International PhD program

  • Kerstin Schmidt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed according to German law and approved by the relevant authorities (Permit numbers: TVA 1188; AZ 55.2-2532-2-485; TVV 41/2016).

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

Publication history

  1. Received: March 23, 2017
  2. Accepted: June 8, 2018
  3. Accepted Manuscript published: June 19, 2018 (version 1)
  4. Version of Record published: June 29, 2018 (version 2)

Copyright

© 2018, Schmidt et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,304
    Page views
  • 390
    Downloads
  • 14
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Stem Cells and Regenerative Medicine
    Diptiman Chanda et al.
    Short Report

    Multicellular organisms maintain structure and function of tissues/organs through emergent, self-organizing behavior. In this report, we demonstrate a critical role for lung mesenchymal stromal cell (L-MSC) aging in determining the capacity to form three-dimensional organoids or ‘alveolospheres’ with type 2 alveolar epithelial cells (AEC2s). In contrast to L-MSCs from aged mice, young L-MSCs support the efficient formation of alveolospheres when co-cultured with young or aged AEC2s. Aged L-MSCs demonstrated features of cellular senescence, altered bioenergetics, and a senescence-associated secretory profile (SASP). The reactive oxygen species generating enzyme, NADPH oxidase 4 (Nox4), was highly activated in aged L-MSCs and Nox4 downregulation was sufficient to, at least partially, reverse this age-related energy deficit, while restoring the self-organizing capacity of alveolospheres. Together, these data indicate a critical role for cellular bioenergetics and redox homeostasis in an organoid model of self-organization and support the concept of thermodynamic entropy in aging biology.

    1. Neuroscience
    2. Stem Cells and Regenerative Medicine
    Arantxa Cebrian-Silla et al.
    Research Article Updated

    The ventricular-subventricular zone (V-SVZ), on the walls of the lateral ventricles, harbors the largest neurogenic niche in the adult mouse brain. Previous work has shown that neural stem/progenitor cells (NSPCs) in different locations within the V-SVZ produce different subtypes of new neurons for the olfactory bulb. The molecular signatures that underlie this regional heterogeneity remain largely unknown. Here, we present a single-cell RNA-sequencing dataset of the adult mouse V-SVZ revealing two populations of NSPCs that reside in largely non-overlapping domains in either the dorsal or ventral V-SVZ. These regional differences in gene expression were further validated using a single-nucleus RNA-sequencing reference dataset of regionally microdissected domains of the V-SVZ and by immunocytochemistry and RNAscope localization. We also identify two subpopulations of young neurons that have gene expression profiles consistent with a dorsal or ventral origin. Interestingly, a subset of genes are dynamically expressed, but maintained, in the ventral or dorsal lineages. The study provides novel markers and territories to understand the region-specific regulation of adult neurogenesis.