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
-
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.
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
© 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
-
- 3,161
- views
-
- 500
- downloads
-
- 33
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Genetics and Genomics
- Stem Cells and Regenerative Medicine
Retinal degeneration in mammals causes permanent loss of vision, due to an inability to regenerate naturally. Some non-mammalian vertebrates show robust regeneration, via Muller glia (MG). We have recently made significant progress in stimulating adult mouse MG to regenerate functional neurons by transgenic expression of the proneural transcription factor Ascl1. While these results showed that MG can serve as an endogenous source of neuronal replacement, the efficacy of this process is limited. With the goal of improving this in mammals, we designed a small molecule screen using sci-Plex, a method to multiplex up to thousands of single-nucleus RNA-seq conditions into a single experiment. We used this technology to screen a library of 92 compounds, identified, and validated two that promote neurogenesis in vivo. Our results demonstrate that high-throughput single-cell molecular profiling can substantially improve the discovery process for molecules and pathways that can stimulate neural regeneration and further demonstrate the potential for this approach to restore vision in patients with retinal disease.
-
- Stem Cells and Regenerative Medicine
Adult mammals, unlike some lower organisms, lack the ability to regenerate damaged hearts through cardiomyocytes (CMs) dedifferentiation into cells with regenerative capacity. Developing conditions to induce such naturally unavailable cells with potential to proliferate and differentiate into CMs, that is, regenerative cardiac cells (RCCs), in mammals will provide new insights and tools for heart regeneration research. In this study, we demonstrate that a two-compound combination, CHIR99021 and A-485 (2C), effectively induces RCCs from human embryonic stem cell-derived TNNT2+ CMs in vitro, as evidenced by lineage tracing experiments. Functional analysis shows that these RCCs express a broad spectrum of cardiogenesis genes and have the potential to differentiate into functional CMs, endothelial cells, and smooth muscle cells. Importantly, similar results were observed in neonatal rat CMs both in vitro and in vivo. Remarkably, administering 2C in adult mouse hearts significantly enhances survival and improves heart function post-myocardial infarction. Mechanistically, CHIR99021 is crucial for the transcriptional and epigenetic activation of genes essential for RCC development, while A-485 primarily suppresses H3K27Ac and particularly H3K9Ac in CMs. Their synergistic effect enhances these modifications on RCC genes, facilitating the transition from CMs to RCCs. Therefore, our findings demonstrate the feasibility and reveal the mechanisms of pharmacological induction of RCCs from endogenous CMs, which could offer a promising regenerative strategy to repair injured hearts.
