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.
Highlights
Because multicellular organisms often face disturbances in their homeostasis, they evolved complex immune responses to deal with sterile and infectious insults
We further demonstrate that the subtype-specific function of H1 in neutrophil and eosinophil differentiation depends – at least in part – on the transcription factor GATA-2
We identified an unexpected role of H1 subtypes in neutrophil development; loss of H1.2 and H1.4 inhibits differentiation while deficiency in H1.1, H1.3 and H1.5 enhances it
Summary
Because multicellular organisms often face disturbances in their homeostasis, they evolved complex immune responses to deal with sterile and infectious insults. Like elsewhere in the human body, immune cells differentiate from multipotent precursors. Precursors are primarily hematopoietic stem cells in the bone marrow. One of these differentiation programs, called granulopoiesis, leads to the development of granulocytes - basophils, eosinophils and neutrophils. Neutrophils are the most abundant leukocytes in humans. Up to 2 Â 1011 neutrophils enter the blood stream per day and patrol the host’s body until they sense signs of infection, which triggers them to leave the blood stream and migrate to the inflammatory site where they ensure pathogen removal. An efficient neutrophil response is crucial for human antimicrobial defense and, correspondingly, neutropenia is associated with severe infections (Klein, 2011)
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