PUBLICATION

Single-cell ATAC-seq reveals GATA2-dependent priming defect in myeloid and a maturation bottleneck in lymphoid lineages

Authors
Avagyan, S., Weber, M.C., Ma, S., Prasad, M., Mannherz, W.P., Yang, S., Buenrostro, J.D., Zon, L.I.
ID
ZDB-PUB-210629-8
Date
2021
Source
Blood advances   5: 2673-2686 (Journal)
Registered Authors
Zon, Leonard I.
Keywords
none
Datasets
GEO:GSE151230, GEO:GSE151232, GEO:GSE151231
MeSH Terms
  • Animals
  • Chromatin Immunoprecipitation Sequencing*
  • GATA2 Deficiency*
  • Lymphopoiesis
  • Transcription Factors/genetics
  • Zebrafish/genetics
PubMed
34170284 Full text @ Blood Adv
Abstract
Germline heterozygous mutations in GATA2 are associated with a syndrome characterized by cytopenias, atypical infections, and increased risk of hematologic malignancies. Here, we generated a zebrafish mutant of gata2b that recapitulated the myelomonocytopenia and B-cell lymphopenia of GATA2 deficiency syndrome. Using single-cell assay for transposase accessible chromatin with sequencing of marrow cells, we showed that loss of gata2b led to contrasting alterations in chromosome accessibility in early myeloid and lymphoid progenitors, associated with defects in gene expression. Within the myeloid lineage in gata2b mutant zebrafish, we identified an attenuated myeloid differentiation with reduced transcriptional priming and skewing away from the monocytic program. In contrast, in early lymphoid progenitors, gata2b loss led to accumulation of B-lymphoid transcription factor accessibility coupled with increased expression of the B-cell lineage-specification program. However, gata2b mutant zebrafish had incomplete B-cell lymphopoiesis with loss of lineage-specific transcription factor accessibility in differentiating B cells, in the context of aberrantly reduced oxidative metabolic pathways. Our results establish that transcriptional events in early progenitors driven by Gata2 are required to complete normal differentiation.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping