| First Author | Muench DE | Year | 2020 |
| Journal | Nature | Volume | 582 |
| Issue | 7810 | Pages | 109-114 |
| PubMed ID | 32494068 | Mgi Jnum | J:294099 |
| Mgi Id | MGI:6446367 | Doi | 10.1038/s41586-020-2227-7 |
| Citation | Muench DE, et al. (2020) Mouse models of neutropenia reveal progenitor-stage-specific defects. Nature 582(7810):109-114 |
| abstractText | 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. |
