Browsing by Author "Carolyn Lutzko"

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    Mouse models of neutropenia reveal progenitor-stage-specific defects
    (2020-01-01) 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; H. Leighton Grimes; BioLegend, Inc.; University of California, San Diego; Cincinnati Children's Hospital Medical Center; University of Cincinnati; Faculty of Medicine, Ramathibodi Hospital, Mahidol University; Fox Chase Cancer Center; Rady Children's Hospital
    © 2020, The Author(s), under exclusive licence to Springer Nature Limited. 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.