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Status |
Public on Apr 06, 2020 |
Title |
Mouse models of neutropenia reveal progenitor-stage-specific defects [scATAC-Seq] |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Advances in genetics and sequencing have lead to a deluge of disease-associated and disease-causing genetic alterations. Resolving causality between genetics and disease requires generating accurate models for molecular dissection; however, the rapid expansion of single-cell landscapes presents a major challenge to accurate comparisons between mutants and their wild type equivalents. Here, we generated mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the Growth factor independent-1 (GFI1) transcription factor. To delineate the impact of SCN mutations, we first generated single-cell references for granulopoietic genomic states with linked epitopes, then developed a new computational approach to align mutant cells to their wild-type equivalent and derive differentially expressed genes. Surprisingly, the majority of differentially expressed GFI1-target genes are sequentially altered as cells traverse successive states. These cell-state-specific insights facilitated genetic rescue of granulocytic specification but not post-commitment defects in the expression of innate-immune effectors, providing regulatory insights into granulocyte dysfunction.
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Overall design |
Single cell ATAC-seq of Gfi1 wild-type and SCN R412X mutant model from combined modified GMP and Ly6g gates
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Contributor(s) |
Muench DE, Olsson A, Chetal K, Salomonis N, Grimes HL |
Citation(s) |
32494068 |
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Submission date |
Dec 19, 2019 |
Last update date |
Jul 07, 2020 |
Contact name |
H. Leighton Grimes |
E-mail(s) |
Lee.Grimes@cchmc.org
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Phone |
513-636-6089
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Organization name |
Cincinnati Childrens Hospital Medical Center
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Department |
Immunobiology
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Lab |
Grimes
|
Street address |
3333 Burnet Ave. MLC 7038
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City |
Cincinnati |
State/province |
OH |
ZIP/Postal code |
45229 |
Country |
USA |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (3) |
GSM4226308 |
Gfi1 wild-type 10x scATAC-Seq replicate 1 |
GSM4226309 |
Gfi1 wild-type 10x scATAC-Seq replicate 2 |
GSM4226310 |
Gfi1 wild-type 10x scATAC-Seq replicate 3 |
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This SubSeries is part of SuperSeries: |
GSE120409 |
A neutropenia-associated transcription factor mutation differentially impacts target genes in the cell-states traversed during granulocyte specification and commitment |
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Relations |
BioProject |
PRJNA596750 |
SRA |
SRP238232 |