The H3K4 methyltransferase Setd1b is essential for hematopoietic stem and progenitor cell homeostasis in mice
- Technische Universität Dresden, Germany
- University Hospital Ulm, Germany
- Hospital of the Universities Giessen and Marburg, Germany
- Friedrich Alexander Universität Erlangen, Germany
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
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Expression profile of hematopoietic stem and progenitor cells (HSPCs) after conditional deletion of the histone 3 lysine 4 (H3K4) methyltransferase Setd1b in micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE97976).
Article and author information
Author details
Konstantinos Anastassiadis
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.
Reviewing Editor
- Amy J Wagers, Harvard University, United States
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).
Version history
- Received: March 23, 2017
- Accepted: June 8, 2018
- Accepted Manuscript published: June 19, 2018 (version 1)
- 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.
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The H3K4 methyltransferase Setd1b is essential for hematopoietic stem and progenitor cell homeostasis in mice
eLife 7:e27157.
https://doi.org/10.7554/eLife.27157
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