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Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.
Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.
The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.
“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”
Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.
“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”
For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.
The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.
Dynamic instability
Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.
Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.
These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.
The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.
Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.
As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.
The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates. 
Image by Volker Brinkmann
Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.
Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.
The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.
“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”
Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.
“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”
For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.
The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.
Dynamic instability
Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.
Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.
These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.
The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.
Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.
As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.
The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates.
Image by Volker Brinkmann
Developing blood cells are caught in a tug of war between competing gene regulatory networks before finally deciding what type of cell to become, according to a study published in Nature.
Researchers found that, as developing blood cells are triggered by a multitude of genetic signals firing on and off, they are pulled back and forth in fluctuating multi-lineage states before finally becoming specific cell types.
The team still doesn’t understand exactly what drives the cells to an eventual fate, but their work suggests that competing gene networks induce dynamic instability, resulting in mixed-lineage states that are necessary to prime newly forming cells for that decision.
“It is somewhat chaotic, but, from that chaos, results order,” said study author Harinder Singh, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“It’s a finding that helps us address a fundamental question of developmental biology: What are the nature of the intermediate states and the networks of regulatory genes that underlie cell-type specification?”
Although the finding requires additional study to better understand the back-and-forth nature of this process, the research may eventually provide new insights into developmental miscues that cause disease, according to study author H. Leighton Grimes, PhD, of Cincinnati Children’s.
“How do blood cells know to become neutrophils or monocytes?” Dr Grimes asked. “Two thirds of your bone marrow is taken up with this activity, and the number of cells has to be exquisitely balanced. Too many or too few of either can kill you.”
For this study, Dr Grimes and his colleagues looked specifically at the formation of neutrophils and macrophages. The researchers studied mouse cells as they developed in a natural state using single-cell RNA sequencing.
The team also used a bioinformatics computer program known as iterative clustering and guide-gene selection (ICGS). They used ICGS to process and analyze sequencing and biological data to identify the various transitioning or shifting genomic and cellular states of developing blood cells.
Dynamic instability
Researchers previously proposed that neutrophils and macrophages result from a bi-stable gene regulatory network—one that can manifest either of 2 stable states. But the different cellular transition states and underlying molecular dynamics of development have remained unknown.
Dr Grimes and his colleagues said their analysis of developing blood cells captured a prevalent mixed-lineage intermediate.
These intermediates expressed a combination of genes, including those typical of hematopoietic stem and progenitor cells and some genes that are specific for red blood cells, platelets, macrophages, and neutrophils. This seemed to reflect competing genetic programs.
The researchers also observed the developing cells moving through a rare state where they encountered turbulence known as dynamic instability. This was caused by 2 counteracting myeloid gene regulatory networks.
Two key components of the counteracting gene networks were Irf8 and Gfi1, genes that are involved in blood cell formation. When Irf8 and Gfi1 were eliminated from the picture, the rare cells could be trapped in an intermediate state.
As they continue this work, the researchers want to gain a clearer understanding of what finally causes cells in intermediate states of dynamic instability to assume specific fates.
The team suggests the influence of 2 simultaneous and counteracting gene networks generates internal oscillations that are eventually stabilized by unknown mechanisms to generate 1 of 2 different cell fates.