Linker histones H1.2 and H1.4 control neutrophil development

Researchers discover new role of DNA-packing proteins for development of immune cells

A small wound is enough: Once the protective layer of our skin is breached, bacteria and other pathogens can enter the body and cause inflammation. Neutrophils are one of the most important cell types for a fast immune reaction. These mobile cells circulate in the blood and, in the event of an inflammation, migrate into the tissue to detect invading pathogens. Once they discover an intruder, neutrophils have diverse defence mechanisms at hand: they can "eat up" bacteria, release toxic substances or even eject their DNA like nets to trap pathogens.

To develop their special abilities, neutrophils undergo a differentiation process called granulopoiesis. During granulopoiesis it is decided which type of granulocyte immune cell develops from a precursor cell. How this decision is made and which factors play a role in the development of neutrophils is not yet completely understood. To answer this question, Arturo Zychlinsky's research group at the Max Planck Institute for Infection Biology in Berlin carried out a genetic screen. The group has now published the results of the study in the journal eLlife.

20,000 genes - 20,000 potential hits

The study was based on a human cell type that can be cultivated in the laboratory and, under the right conditions, develop into a cell that closely resembles a neutrophil. Using the CRISPR/Cas9 system, the researchers switched off each of the 20,000 human genes in this cell type. In this way, they wanted to find out which genes play an important role in the differentiation and function of neutrophils. If cells did not develop into a neutrophil in the experiment, the scientists were able to determine which gene was switched off: this gene was possibly involved in the differentiation process.

"Often not what you would have expected"

The subsequent analysis of the experiments surprised the researchers. "At first we thought the result was not specific. Our top hit was a gene for a linker histone, a protein that has never before been associated with the development of neutrophils," said Gabriel Sollberger, lead author of the study. "When you do such a broad analysis, the result is often not what you would have expected. Nevertheless, we were amazed to find something completely new."

Among the top hits were genes for the linker histones H1.2 and H1.4. Histones are proteins used to package DNA. More than two meters of DNA need to fit in cells of only a few micrometres in diameter. To do this, the DNA wraps itself around histone proteins like a thread. Linker histones lie between the histone DNA packages–they help to pack these clusters even closer together.

Setting the course for development

It was not known before that the linker histones H1.2 and H1.4 also control the development of neutrophils. If one of the two proteins is missing, no neutrophils develop from the precursor cells in culture. The reason for this seems to be the control of the transcription factors GATA-1 and GATA-2, which the linker histones suppress. If a lot of GATA-2 is present, the cells take a different path during granulopoiesis and develop in the direction of eosinophils. Although this cell type is closely related to neutrophils, it performs other tasks, such as defence against parasites.

New fields of research

The work of Arturo Zychlinsky’s team opens a new perspective on the differentiation of neutrophils. It may be possible to attribute disturbances in granulopoiesis to defects in the linker histones that were previously ignored. Hematopoiesis is part of the formation of blood cells, during which immune cells develop. Here, too, linker histones could take on a previously unknown control function. In addition, it remains open by which molecular process the linker histones suppress the transcription factors GATA-1 and -2. These questions will be pursued in future studies.