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

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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

1. Anastassiadis K
2. Schmidt K
(2017) Expression profile of hematopoietic stem and progenitor cells (HSPCs) after conditional deletion of the histone 3 lysine 4 (H3K4) methyltransferase Setd1b in mice
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE97976).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE97976

Article and author information

Author details

Kerstin Schmidt

Stem Cell Engineering, Biotechnology Center, Technische Universität Dresden, Dresden, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9596-4026
Qinyu Zhang

Genomics, Biotechnology Center, Technische Universität Dresden, Dresden, Germany

Competing interests
The authors declare that no competing interests exist.
Alpaslan Tasdogan

Institute of Immunology, University Hospital Ulm, Ulm, Germany

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.
Robert Slany

Department of Genetics, Friedrich Alexander Universität Erlangen, Erlangen, Germany

Competing interests
The authors declare that no competing interests exist.
Hans Jörg Fehling

Institute of Immunology, University Hospital Ulm, Ulm, Germany

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.

"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).

Copyright

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.