Mouse Models of Neutropenia Reveal Progenitor-Stage-Specific Defects

David E Muench1,2, Andre Olsson1, Kyle Ferchen1,3, Giang Pham4, Rachel A Serafin1, Somchai Chutipongtanate3,5, Pankaj Dwivedi3, Baobao Song1,6, Stuart Hay7, Kashish Chetal7, Lisa R Trump-Durbin8, Jayati Mookerjee-Basu9, Kejian Zhang10,11, Jennifer C Yu12,13, Carolyn Lutzko8,11, Kasiani C Myers11,14, Kristopher L Nazor15, Kenneth D Greis3, Dietmar J Kappes9, Sing Sing Way4,11, Nathan Salomonis16,17, H Leighton Grimes18,19,20

  1. Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  2. Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  3. Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
  4. Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  5. Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
  6. Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  7. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  8. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  9. Fox Chase Cancer Center, Philadelphia, PA, USA.
  10. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  11. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
  12. Division of Pediatric Hematology/Oncology, Rady Children's Hospital San Diego, San Diego, CA, USA.
  13. Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
  14. Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  15. BioLegend, Inc., San Diego, CA, USA.
  16. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. nathan.salomonis@cchmc.org.
  17. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA. nathan.salomonis@cchmc.org.
  18. Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. lee.grimes@cchmc.org.
  19. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. lee.grimes@cchmc.org.
  20. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA. lee.grimes@cchmc.org.

Abstract

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 epitopes1, 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.

In this talk: Single-cell Analysis of Mixed-Lineage States Leading to a Binary Cell Fate Choice

Nature. 2016 Sep 29;537(7622):698-702. doi: 10.1038/nature19348. | PubMed

Andre Olsson, Meenakshi Venkatasubramanian, Viren K Chaudhri ... Nathan Salomonis, Harinder Singh, H Leighton Grimes


Presented By H Leighton Grimes

Initially presented as a Blood and Bones seminar.

Cell & Developmental Bio, Genomics, MedicineNicholas Liao2020-06 (Jun)