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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Mouse models of neutropenia reveal progenitor-stage-specific defects.

Authors: Muench, David E; Olsson, Andre; Ferchen, Kyle; Pham, Giang; Serafin, Rachel A; Chutipongtanate, Somchai; Dwivedi, Pankaj; Song, Baobao; Hay, Stuart; Chetal, Kashish; Trump-Durbin, Lisa R; Mookerjee-Basu, Jayati; Zhang, Kejian; Yu, Jennifer C; Lutzko, Carolyn; Myers, Kasiani C; Nazor, Kristopher L; Greis, Kenneth D; Kappes, Dietmar J; Way, Sing Sing; Salomonis, Nathan; Grimes, H Leighton

Published In Nature, (2020 06)

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.

PubMed ID: 32494068 Exiting the NIEHS site

MeSH Terms: Animals; Candida albicans/immunology; Candida albicans/pathogenicity; Cell Lineage; DNA-Binding Proteins/genetics; Disease Models, Animal*; Female; Granulocyte Precursor Cells/pathology*; Humans; Immunity, Innate; Male; Mice; Mice, Transgenic; Mutation*; Neutropenia/congenital; Neutropenia/genetics*; Neutropenia/immunology; Neutropenia/pathology*; Neutrophils/immunology; Neutrophils/pathology*; Transcription Factors/genetics

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