Understanding granulocyte homeostasis is crucial because producing too few granulocytes results in increased risk for infection (neutropenia), while producing too many granulocytes can result in severe tissue damage and death (neutrophilia, myeloproliferative disorders). Current knowledge illustrates many factors that can modify granulocyte versus monocyte production; however, we still do not understand a fundamental question: which specific factors control the granulocyte-monocyte lineage decision during homeostatic production in vivo? To discern the transcriptional network underlying the binary fate decision between neutrophil granulocyte and monocyte lineage decisions as they occur at steady state (homeostatic control), we have performed single-cell RNA-seq on bone-marrow granulocyte-monocyte progenitors (GMP). Our bioinformatic analyses reveal a varied, but coherent spectrum of gene expression patterns in individual murine GMPs. The majority of cells could be clustered into ones expressing either granulocytic or monocytic genes, suggesting that they were primed for lineage determination. A minority of GMPs expressed a mixed-lineage pattern of genes. Deeper analyses of the single-cell data implicate the repression of a key requisite factor for monopoiesis in mice and man (Irf8) by a key requisite factor for granulopoiesis in mice and man (Gfi1) as the central mechanism for homeostatic control of the granulocyte-monocyte lineage decision in vivo. We propose to determine the transcriptional program underlying granulocyte-monocyte lineage fate decisions during homeostasis, and then define the impact of severe congenital neutropenia (SCN)-associated mutations on transcriptional control of granulopoiesis in mice and man. We expect to delineate a cross-species transcriptional signature of granulopoiesis, and define the impact of neutropenic stress.

Public Health Relevance

Understanding the cellular and molecular processes underlying granulocyte homeostasis is crucial because producing too few granulocytes results in increased risk for infection (neutropenia), while producing too many granulocytes can result in severe tissue damage and death (neutrophilia, myeloproliferative disorders). This project will determine which specific factors control the granulocyte-monocyte lineage decision in vivo, and will illustrate the pivotal transcriptional networks controlling homeostatic granulocyte production and their deregulation during neutropenic stress.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122661-03
Application #
9263013
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Yang, Yu-Chung
Project Start
2015-07-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Lee, Jung-Mi; Govindarajah, Vinothini; Goddard, Bryan et al. (2018) Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression. J Exp Med 215:627-644
Yáñez, Alberto; Coetzee, Simon G; Olsson, Andre et al. (2017) Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes. Immunity 47:890-902.e4
Olsson, Andre; Venkatasubramanian, Meenakshi; Chaudhri, Viren K et al. (2016) Single-cell analysis of mixed-lineage states leading to a binary cell fate choice. Nature 537:698-702