|
| Status |
Public on Aug 24, 2023 |
| Title |
ETV6 Represses Inflammatory Response Genes and Regulates HSPC Function During Stress Hematopoiesis in Mice |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Other
Expression profiling by high throughput sequencing
|
| Summary |
This SuperSeries is composed of the SubSeries listed below.
ETS Variant 6 (ETV6) encodes an essential transcriptional repressor abundantly expressed in hematopoietic stem and progenitor cells (HSPCs), where it is required for adult hematopoiesis. Heterozygous pathogenic germline ETV6 variants are associated with Thrombocytopenia 5 (T5), a poorly understood genetic condition predisposing to thrombocytopenia and hematologic malignancies. To elucidate how germline ETV6 variants impact the HSPC compartment and contribute to disease, we generated a knock-in mouse model harboring an Etv6R355X loss-of-function variant, which is equivalent to the T5-associated variant ETV6R359X. Under homeostatic conditions, all HSPC subpopulations are present in the bone marrow (BM) of Etv6R355X/+ mice; however, these animals display subtle shifts in the proportions and/or numbers of specific progenitor subtypes. To examine whether the Etv6R355X/+ mutation impacts HSPC function, we carried out serial competitive transplantation and observed that Etv6R355X/+ lineage-sca1+cKit+ (LSK) cells exhibit significantly impaired reconstitution compared to Etv6+/+ LSK cells with near complete failure to repopulate irradiated-recipients by the tertiary transplant. Mechanistic studies incorporating CUT&RUN, ATAC-Seq and Hi-C identify ETV6 binding at inflammatory gene loci, including those within the TNF signaling pathway, in Etv6+/+ HSPCs, mouse BM-progenitor-derived HPC5 cells, and human CD34+ cells. Further, single-cell RNA-Seq of BM cells isolated post-competitive transplantation reveals upregulation of inflammatory genes in Etv6R355X/+ compared to Etv6+/+ progenitors. Corroborating these findings, Etv6R355X/+ HSPCs produce significantly more TNF than Etv6+/+ cells post-transplantation. From these studies, we conclude that ETV6 is required to repress inflammatory gene expression in HSPCs under conditions of hematopoietic stress and this mechanism may be critical to sustain HSPC function.
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| Overall design |
Refer to individual Series
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| |
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| Citation(s) |
37522715 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA241452 |
Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia |
ST. JUDE CHILDREN'S RESEARCH HOSPITAL |
KIM Erika NICHOLS |
| F31 HL154645 |
Role of the ETV6 transcription factor in hematopoietic stem cell function |
ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC |
Mackenzie Bloom |
|
| BioProject |
PRJNA880871 |
| |
| Submission date |
Sep 18, 2022 |
| Last update date |
Feb 28, 2024 |
| Contact name |
Kim Nichols |
| E-mail(s) |
[email protected]
|
| Organization name |
St. Jude Children's Research Hospital
|
| Department |
Oncology
|
| Lab |
Nichols Lab
|
| Street address |
262 Danny Thomas Pl
|
| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38105 |
| Country |
USA |
| |
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| Platforms (3) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (27)
|
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| This SuperSeries is composed of the following SubSeries:
|
| GSE213593 |
ETV6 Represses Inflammatory Response Genes and Regulates HSPC Function During Stress Hematopoiesis in Mice [ATAC-seq] |
| GSE213594 |
ETV6 Represses Inflammatory Response Genes and Regulates HSPC Function During Stress Hematopoiesis in Mice [CUT&RUN] |
| GSE213595 |
ETV6 Represses Inflammatory Response Genes and Regulates HSPC Function During Stress Hematopoiesis in Mice [Hi-C] |
| GSE213596 |
ETV6 Represses Inflammatory Response Genes and Regulates HSPC Function During Stress Hematopoiesis in Mice [RNA-seq] |
| GSE233968 |
ETV6 Represses Inflammatory Response Genes and Regulates HSPC Function During Stress Hematopoiesis in Mice [scRNA-seq] |
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