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| Status |
Public on Apr 15, 2024 |
| Title |
A critical requirement for IκBα in controlling dormancy in Hematopoietic stem cells via retinoic acid during embryonic development [Cut&Tag] |
| Organism |
Mus musculus |
| Experiment type |
Other
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Hematopoietic Stem Cells (HSCs) originate from the E11.5 aorta-gonads-and mesonephros (AGM) region during development before they migrate to the foetal liver for proliferation and maturation, and finally seed the bone marrow around birth, their final site of residence. In the AGM, HSCs reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). Molecular pathways that determine HSC fate instead of HPCs are still unknown, although inflammatory signalling has been implicated in the development of all blood cells, including NF-κB. Here, we describe a dormant phenotype of LT-HSCs in the IκBα KO. Although IκBα is critical for retaining inactive NF-κB complexes in the cytoplasm, it can regulate stem cell related genes by interacting with the PRC2 complex in the nucleus. Accordingly, we find decreased PRC2 dependent H3K27me3 accumulation at the promoters of PI3K and retinoic acid signalling molecules by cut and tag assay in AGM derived CD31+ cells, which includes HE/IAHC derived from IκBα KO embryos. Furthermore, this regulation of the retinoic acid signalling by IκBα is further confirmed by cut and tag assay for IκBα itself in CD31+ cells of the AGM and more specifically also in sorted LT-HSCs from the E14.5 foetal liver. Over-activation of the retinoic acid/PI3K levels in LT-HSCs of the IκBα KO is evident in their dormant molecular profile. Functionally, IκBα KO LT-HSCs are less proliferative and respond with delayed activation upon transplantation. Overall, we identify nuclear IκBα as an essential player specifically for HSC specification/proliferation from the onset of HSPC emergence in the AGM.
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| Overall design |
We performed cut&tag assay for H3K27me3 (IkBa Ko and WT) and Ikba with sorted embryonic fetal liver (E14.5 LT-HSCs) or AGM (E11.5 CD31+). Specifically, we generated 2 replicates from fetal liver and 2 replicates from AGM for IkBa Cut&Tag experiments. Regarding H3K27me3 experiments, replicates were only generated for E14.5 FL-HSCs and considered 3xIkBa WT and 3xIkBa KO.
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| Contributor(s) |
Thambyrajah R, Maqueda M, Fadlullah Z, Proffitt M, Hao N, Guillén Y, Casado-Pelaez M, Herrero-Molinero P, Brujas C, Castelluccio N, González J, Iglesias A, Marruecos L, Ruiz-Herguido C, Esteller M, Mereu E, Lacaud G, Espinosa L, Bigas A |
| Citation(s) |
38824124 |
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| Submission date |
Nov 10, 2021 |
| Last update date |
Jun 26, 2024 |
| Contact name |
Anna Bigas |
| E-mail(s) |
abigas@imim.es
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| Phone |
+34933160440
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| Organization name |
Institut Hospital del Mar d'Investigacions Mèdiques
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| Department |
Cancer Research
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| Lab |
Stem Cells and Cancer
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| Street address |
Dr. Aiguader 88
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| City |
Barcelona |
| State/province |
Barcelona |
| ZIP/Postal code |
08003 |
| Country |
Spain |
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| Platforms (3) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (10)
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| This SubSeries is part of SuperSeries: |
| GSE188525 |
A critical requirement for IκBα in controlling dormancy in Hematopoietic stem cells via retinoic acid during embryonic development |
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| Relations |
| BioProject |
PRJNA779270 |
| SRA |
SRP345391 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE188524_RAW.tar |
1.2 Gb |
(http)(custom) |
TAR (of BED, BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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