PUBLICATION
Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency
- Authors
- Mahony, C.B., Copper, L., Vrljicak, P., Noyvert, B., Constantinidou, C., Browne, S., Pan, Y., Palles, C., Ott, S., Higgs, M.R., Monteiro, R.
- ID
- ZDB-PUB-230601-38
- Date
- 2023
- Source
- Cell Reports 42: 112571112571 (Journal)
- Registered Authors
- Monteiro, Rui
- Keywords
- CP: Molecular biology, CP: Stem cell research, DNA damage, GATA2 deficiency, hematopoietic stem cells, single-cell genomics, zebrafish
- MeSH Terms
-
- Bone Marrow Failure Disorders
- Genomic Instability
- GATA2 Transcription Factor/genetics
- GATA2 Transcription Factor/metabolism
- Bone Marrow*/metabolism
- Zebrafish/metabolism
- Animals
- GATA2 Deficiency*
- PubMed
- 37256751 Full text @ Cell Rep.
Citation
Mahony, C.B., Copper, L., Vrljicak, P., Noyvert, B., Constantinidou, C., Browne, S., Pan, Y., Palles, C., Ott, S., Higgs, M.R., Monteiro, R. (2023) Lineage skewing and genome instability underlie marrow failure in a zebrafish model of GATA2 deficiency. Cell Reports. 42:112571112571.
Abstract
Inherited bone marrow failure associated with heterozygous mutations in GATA2 predisposes toward hematological malignancies, but the mechanisms remain poorly understood. Here, we investigate the mechanistic basis of marrow failure in a zebrafish model of GATA2 deficiency. Single-cell transcriptomics and chromatin accessibility assays reveal that loss of gata2a leads to skewing toward the erythroid lineage at the expense of myeloid cells, associated with loss of cebpa expression and decreased PU.1 and CEBPA transcription factor accessibility in hematopoietic stem and progenitor cells (HSPCs). Furthermore, gata2a mutants show impaired expression of npm1a, the zebrafish NPM1 ortholog. Progressive loss of npm1a in HSPCs is associated with elevated levels of DNA damage in gata2a mutants. Thus, Gata2a maintains myeloid lineage priming through cebpa and protects against genome instability and marrow failure by maintaining expression of npm1a. Our results establish a potential mechanism underlying bone marrow failure in GATA2 deficiency.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping