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Cell fate a result of genetic tugs of war

Developing blood cells are caught in a tug of war between competing gene networks to decide what cell type each will become.

According to a study published Aug. 31 in Nature magazine, researchers at Cincinnati Children's Hospital Medical Center report that developing blood cells are tugged at by multipule genetic signals firing on and off, pulling them back and forth before they finally become specific cell types.

Although scientists still don't understand exactly what determines the final fate of a cell, the research suggests competition between gene networks creates instability, which primes new cells towards a final decision.

"It is somewhat chaotic, but from that chaos comes order. It's a finding that helps us address a fundamental question in developmental biology — 'What is the nature of cellular intermediate states and the networks of regulatory genes that underlie cell specification?'"

Harinder Singh PhD, Director, Immunobiology, Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Ohio, USA, and study co-author.

Although the results of the research require more study to understand what is behind the back-and-forth nature of this gene process, researchers may eventually gain insight into those miscues causing disease.

"How do blood cells know to become neutrophils or monocytes? 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."

H. Leighton Grimes PhD, Investigator, Divisions of Immunobiology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Ohio, USA, and study co-author.

In this current study, researchers looked specifically at the formation of neutrophil and monocyte (macrophage) blood cells — critical components of our immune system. Using a new technology called single-cell RNA sequencing — which identifies the genetic expression of individual cells and the presumed influences regulating them— they studied mouse blood cells.

Blending laboratory biology with a new bioinformatics computer program named Iterative Clustering and Guide-Gene Selection (ICGS), along with co-author Nathan Salomonis PhD, they developed an in-depth view of the overwhelming amount of data generated by single-cell RNA sequencing.

ICGS gives research an intuitive platform to process and analyze all of the sequencing and biological data of various transitions and shifting gene and cell states in our developing blood cells.

Prior to this study it was proposed that neutrophil and macrophage blood cells result from a bi-stable (meaning: either of two stable states) gene network.

Working back and forth between laboratory biology and computational analysis, researchers in the current paper captured a mixed-lineage intermediate state of blood cells. These intermediate cells expressed a combination of genes including those of typical stem cells that can give rise to all blood cell types, as well as some genes found only in red blood cells, platelets, macrophages and neutrophils. This suggests competing genetic programs.

The team found developing cells moved through a rare state of turbulence they called "dynamic instability,"
caused by two counteracting myeloid gene regulatory networks. There are two key genes — Irf8 and Gfi1 — implicated in these blood cell networks.

Both of the Irf8 and Gfi1 genes encode transcription factors, this means the proteins they produce control the genes forming a cell.

When Irf8 and Gfi1 genes were eliminated, researchers saw cells trapped in rare intermediate states.

The authors went looking for what ultimately causes cells to go from intermediate states into one specific state. Believing that simultaneous and counteracting gene networks generate oscillations which will eventually stabilize into one cell fate, they may have found part of their answer in the Irf8 and Gfi1 genes.

Delineating hierarchical cellular states, including rare intermediates and the networks of regulatory genes that orchestrate cell-type specification, are continuing challenges for developmental biology. Single-cell RNA sequencing is greatly accelerating such research, given its power to provide comprehensive descriptions of genomic states and their presumptive regulators1, 2, 3, 4, 5. Haematopoietic multipotential progenitor cells, as well as bipotential intermediates, manifest mixed-lineage patterns of gene expression at a single-cell level6, 7. Such mixed-lineage states may reflect the molecular priming of different developmental potentials by co-expressed alternative-lineage determinants, namely transcription factors. Although a bistable gene regulatory network has been proposed to regulate the specification of either neutrophils or macrophages7, 8, the nature of the transition states manifested in vivo, and the underlying dynamics of the cell-fate determinants, have remained elusive. Here we use single-cell RNA sequencing coupled with a new analytic tool, iterative clustering and guide-gene selection, and clonogenic assays to delineate hierarchical genomic and regulatory states that culminate in neutrophil or macrophage specification in mice. We show that this analysis captured prevalent mixed-lineage intermediates that manifested concurrent expression of haematopoietic stem cell/progenitor and myeloid progenitor cell genes. It also revealed rare metastable intermediates that had collapsed the haematopoietic stem cell/progenitor gene expression programme, instead expressing low levels of the myeloid determinants, Irf8 and Gfi1 (refs 9, 10, 11, 12, 13). Genetic perturbations and chromatin immunoprecipitation followed by sequencing revealed Irf8 and Gfi1 as key components of counteracting myeloid-gene-regulatory networks. Combined loss of these two determinants ‘trapped’ the metastable intermediate. We propose that mixed-lineage states are obligatory during cell-fate specification, manifest differing frequencies because of their dynamic instability and are dictated by counteracting gene-regulatory networks.

Funding support for the study came in part from the National Institutes of Health (R01HL122661), the Cincinnati Children's Research Foundation and the Divisions of Oncology and Pathology at Cincinnati Children's.

About Cincinnati Children's
Cincinnati Children's, a non-profit, pediatric, academic medical center established in 1883, is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. It is one of the top three recipients of pediatric research grants from the National Institutes of Health, ranked third in the nation among all Honor Roll hospitals in U.S. News and World Report's Best Children's Hospitals, and a research and teaching affiliate of the University of Cincinnati's College of Medicine. Its patient population includes the eight-county primary service area covering parts of Ohio, Kentucky and Indiana. A destination for children with complex medical conditions, it also served patients from all 50 states and nearly 70 countries during the past year. Additional information can be found at http://www.cincinnatichildrens.org. Connect on the Cincinnati Children's blog, via Facebook and on Twitter.

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Sep 8, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Proposed model of "mixed-lineage" cell states as they transition into specialized types of blood cells:
HSCP-Hematopoietic stem cell progenitor
Meg-Megakaryocyte ; Eryth-Erythrocytes normally 45% of blood volume; HSCP-Hematopoetic Stem Cell Progenitor;
Myeloid-myeloid or lymphoid progenitor cell; Mono-Monocyte or leukocyte, largest of White Blood Cells;
Gran-granules which contain enzymes and proteins that neutralize or destroy microorganisms.
Image Credit: Center for Systems Immunology, Cincinnati Children's Hospital, and Nature.com



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