Mouse models of neutropenia reveal progenitor-stage-specific defects

David E. Muench, Andre Olsson, Kyle Ferchen, Giang Pham, Rachel A. Serafin, Somchai Chutipongtanate, Pankaj Dwivedi, Baobao Song, Stuart Hay, Kashish Chetal, Lisa R. Trump-Durbin, Jayati Mookerjee-Basu, Kejian Zhang, Jennifer C. Yu, Carolyn Lutzko, Kasiani C. Myers, Kristopher L. Nazor, Kenneth D. Greis, Dietmar J. Kappes, Sing Sing Way, Nathan Salomonis () and H. Leighton Grimes ()
Additional contact information
David E. Muench: Cincinnati Children’s Hospital Medical Center
Andre Olsson: Cincinnati Children’s Hospital Medical Center
Kyle Ferchen: Cincinnati Children’s Hospital Medical Center
Giang Pham: Cincinnati Children’s Hospital Medical Center
Rachel A. Serafin: Cincinnati Children’s Hospital Medical Center
Somchai Chutipongtanate: University of Cincinnati
Pankaj Dwivedi: University of Cincinnati
Baobao Song: Cincinnati Children’s Hospital Medical Center
Stuart Hay: Cincinnati Children’s Hospital Medical Center
Kashish Chetal: Cincinnati Children’s Hospital Medical Center
Lisa R. Trump-Durbin: Cincinnati Children’s Hospital Medical Center
Jayati Mookerjee-Basu: Fox Chase Cancer Center
Kejian Zhang: Cincinnati Children’s Hospital Medical Center
Jennifer C. Yu: Rady Children’s Hospital San Diego
Carolyn Lutzko: Cincinnati Children’s Hospital Medical Center
Kasiani C. Myers: University of Cincinnati
Kristopher L. Nazor: BioLegend, Inc.
Kenneth D. Greis: University of Cincinnati
Dietmar J. Kappes: Fox Chase Cancer Center
Sing Sing Way: Cincinnati Children’s Hospital Medical Center
Nathan Salomonis: Cincinnati Children’s Hospital Medical Center
H. Leighton Grimes: Cincinnati Children’s Hospital Medical Center

Nature, 2020, vol. 582, issue 7810, 109-114

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2227-7

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