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Series GSE224904 Query DataSets for GSE224904
Status Public on Feb 21, 2023
Title Pathogenic Mutation that Dislocates GATA2 Zinc Fingers Establishes a Hematopoiesis-Disrupting Signaling Network
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary While certain human genetic variants are conspicuously loss-of-function, decoding the functional impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies in Gata2 enhancer-mutant hematopoietic progenitor cells to reveal how the insertion impacts GATA2 function genome-wide. Despite being nuclear-localized, 9aa-Ins was severely defective, with activation more impaired than repression. Variation of the inter-zinc finger spacer length revealed that repression tolerated insertions that were detrimental to activation. GATA2 deficiency generated a hematopoiesis-disrupting signaling network in progenitor cells with reduced Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signaling and elevated Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling causes bone marrow failure, hallmark phenotypes of GATA2-deficiency patients, these results establish molecular mechanisms underlying GATA2-linked pathologies.
Overall design 25000 Hoxb8-immortalized wild type hematopoietic progenitors (hi−77+/+) infected with control (empty) retrovirus, Gata2 -77 enhancer deleted mutant progenitors (hi−77−/−) infected with empty retrovirus or GATA2- or 9aa-Ins-expressing retrovirus were FACS isolated for GFP+
Contributor(s) Jung MM, Olender T, Zhang Q, Brand M, Bresnick EH
Citation(s) 36809258
Submission date Feb 09, 2023
Last update date May 28, 2023
Contact name Marjorie Brand
Phone 613-737-8803
Organization name Ottawa Hospital Research Institute
Department Regenerative Medicine Program
Lab Brand Lab
Street address 501 Smyth Road
City Ottawa
State/province Onatrio
ZIP/Postal code K1H 8L6
Country Canada
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (7)
GSM7035365 anti-GATA2 WT rep1
GSM7035366 anti-GATA2 9aa-Ins rep1
GSM7035367 anti-GATA2 9aa-Ins rep2
BioProject PRJNA933097

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Supplementary file Size Download File type/resource
GSE224904_HA-tag_9aa_RepMerged_MACS3_TF_q1e-6_peaks.narrowPeak.gz 18.6 Kb (ftp)(http) NARROWPEAK
GSE224904_HA-tag_WT_RepMerged_MACS3_TF_q1e-6_peaks.narrowPeak.gz 103.4 Kb (ftp)(http) NARROWPEAK
GSE224904_RAW.tar 422.6 Mb (http)(custom) TAR (of BW)
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Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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