Linker histone H1.2 and H1.4 affect the neutrophil lineage determination
- University of Dundee, United Kingdom
- Max Planck Institute for Infection Biology, Germany
- Max Planck Institute for Molecular Genetics, Germany
- Albert Einstein College of Medicine, United States
Abstract
Neutrophils are important innate immune cells that tackle invading pathogens with different effector mechanisms. They acquire this antimicrobial potential during their maturation in the bone marrow, where they differentiate from hematopoietic stem cells in a process called granulopoiesis. Mature neutrophils are terminally differentiated and short-lived with a high turnover rate. Here, we show a critical role for linker histone H1 on the differentiation and function of neutrophils using a genome-wide CRISPR/Cas9 screen in the human cell line PLB-985. We systematically disrupted expression of somatic H1 subtypes to show that individual H1 subtypes affect PLB-985 maturation in opposite ways. Loss of H1.2 and H1.4 induced an eosinophil-like transcriptional program, thereby negatively regulating the differentiation into the neutrophil lineage. Importantly, H1 subtypes also affect neutrophil differentiation and the eosinophil-directed bias of murine bone marrow stem cells, demonstrating an unexpected subtype-specific role for H1 in granulopoiesis.
Data availability
RNA sequencing data have been deposited in ArrayExpress - accession no. E-MTAB-8459All data generated or analysed during this study are included in the manuscript and supplemental files. Source data files are provided for Figure 1 and Figure 4. A supplementary table with all used qPCR primers, sgRNA sequences, antibodies and other reagents is provided.
Article and author information
Author details
Gabriel Sollberger
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P300P3_158518)
- Gabriel Sollberger
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P2EZP3_148748)
- Gabriel Sollberger
Max-Planck-Gesellschaft
- Robert Streeck
- Brian Edward Caffrey
- Arturo Zychlinsky
National Institute of General Medical Sciences (GM116143)
- Arthur I Skoultchi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Florent Ginhoux, Agency for Science Technology and Research, Singapore
Ethics
Animal experimentation: Breeding of mice and isolation of blood and bone marrow were approved by the Berlin state authority Landesamt für Gesundheit und Soziales. All mice were bred at the Max Planck Insitute for Infection Biology under specific pathogen-free conditions. Animals were maintained on a 12-hour light/12-hour dark cycle and fed ad libitum
Human subjects: Human primary neutrophils, PBMCs and monocytes were isolated from blood samples of healthy volunteers according to the declaration of Helsinki. All donors provided written informed consent and all blood samples were collected with approval from the local ethics committee.
Version history
- Received: October 8, 2019
- Accepted: May 8, 2020
- Accepted Manuscript published: May 11, 2020 (version 1)
- Version of Record published: May 26, 2020 (version 2)
- Version of Record updated: May 27, 2020 (version 3)
Copyright
© 2020, Sollberger 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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Linker histone H1.2 and H1.4 affect the neutrophil lineage determination
eLife 9:e52563.
https://doi.org/10.7554/eLife.52563
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The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.
