Mouse models of neutropenia reveal progenitor-stage-specific defects
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Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes 1, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.
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The coupling of genetic discoveries with single-cell genomic tools greatly increases potential to further refine understanding of hematopoiesis, as has been done in recent studies of congenital neutropenia.
“The coupling of these genetic discoveries with the single-cell genomic tools we have discussed in this review greatly increases our potential to further refine our understanding of hematopoiesis, as has been done elegantly in recent studies of congenital neutropenia (Muench et al., 2020).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Muench et al., 2020
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Slow cycling and durable Flt3+ progenitors contribute to hematopoiesis under native conditions
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Single-Cell RNA Sequencing to Disentangle the Blood System
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Human TLR8 induces inflammatory bone marrow erythromyeloblastic islands and anemia in SLE-prone mice
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ThPOK is a critical multifaceted regulator of myeloid lineage development
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Single-Cell Profiling of Tumor-Associated Neutrophils in Advanced Non-Small Cell Lung Cancer
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The Role of Neutrophil in COVID-19 — Positive or Negative
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Microenvironmental control of hematopoietic stem cell fate via CXCL8 and protein kinase C
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Induced cell-autonomous neutropenia systemically perturbs hematopoiesis in Cebpa enhancer-null mice
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Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic–Epigenetic Cross-Talk
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A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice
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Function of Deptor and its roles in hematological malignancies
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From Defense to Dysfunction: Decoding the Paradox of Emergency Granulopoiesis in Sepsis Pathogenesis
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Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors
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Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer
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The metabolic basis of inherited neutropenias
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Divergent granulopoiesis at extramedullary sites safeguards host defensePreprint
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Why Single-Cell Sequencing Has Promise in MDS
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Harnessing myeloid cell plasticity for cancer therapy
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A Multi-Modal Toolkit for Studying Neutrophils in Cancer and Beyond
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The Role of Neutrophils and NETosis in Diseases: The Implications for Therapy
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Joint Analysis of Transcriptome and Proteome Measurements in Single Cells with totalVI
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- Authors
- Muench, D. E., Olsson, A., Ferchen, K., Pham, G., Serafin, R. A., Chutipongtanate, S., Dwivedi, P., Song, B., Hay, S., Chetal, K., Trump-Durbin, L. R., Mookerjee-Basu, J., Zhang, K., Yu, J. C., Lutzko, C., Myers, K. C., Nazor, K. L., Greis, K. D., Kappes, D. J., Way, S. S., Salomonis, N., & Grimes, H. L.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Mahidol University (TH)
- University of Cincinnati (US)
- University of California San Diego (US)
- BioLegend (United States) (US)
- Fox Chase Cancer Center (US)
- Corresponding author
- Salomonis, Nathan
- Grimes, H. Leighton
- ORCID
- Venue
- Nature
- Published
- 2020-04-22
- Volume
- 582
- Issue
- 7810
- Pages
- 109-114
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8041154
- OpenAlex
- W3018353191
- Cited by
- 115
- References
- 35
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 12 · 2023: 17 · 2022: 20 · 2021: 29 · 2020: 8
- FWCI
- 10.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (DK78392, AR‐47363)
- National Heart, Lung, and Blood Institute (R01HL122661)
- National Cancer Institute (T32CA117846)
- National Institute of Allergy and Infectious Diseases (DP1AI131080)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK090971, P30DK078392)
- National Institute of Environmental Health Sciences (T32ES007250)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR047363)
- National Center for Research Resources (S10RR027015)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Oncology › Neutropenia and Cancer Infections
- Keywords
- severe congenital neutropenia, GFI1, mouse model, granulopoiesis, genetic rescue
- MeSH terms
- Animals, Candida albicans, Disease Models, Animal, DNA-Binding Proteins, Female, Humans, Immunity, Innate, Male, Mice, Transgenic, Mutation, Neutropenia, Neutrophils, Transcription Factors, Cell Lineage, Granulocyte Precursor Cells, Mice
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