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SRX16665163: GSM6387759: RBG25050_WT; Mus musculus; RNA-Seq
1 ILLUMINA (Illumina HiSeq 2500) run: 578,301 spots, 28.9M bases, 11.2Mb downloads

External Id: GSM6387759_r1
Submitted by: Haematology, University of Cambridge
Study: Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner
show Abstracthide Abstract
Aged hematopoietic stem cells (HSC) display diminished self-renewal and a myeloid differentiation bias. However, the physiological drivers and molecular processes that underpin this fundamental switch are not understood. HSCs produce formaldehyde and are protected from this metabolite by two tiers of protection: the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. Using single cell RNA sequencing, we find that the HSC and progenitor cells in young Aldh2-/- Fancd2-/- mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition and myeloid-biased progenitors. In addition, the p53 response is vigorously activated in Aldh2-/- Fancd2-/- HSCs, whilst p53 deletion rescued this aged transcriptomic signature and telomere attrition. Transplantation of single Aldh2-/- Fancd2-/- HSCs also reveals a predominantly myeloid output, which is reversed upon p53 deletion. To further define the origins of the myeloid differentiation bias, a GFP genetic reporter which detects Vwf+ myeloid primed HSCs was crossed into Aldh2-/- Fancd2-/- mice, revealing a striking enrichment of these lineage-biased Vwf+ HSCs. These results indicate that metabolism derived formaldehyde causes endogenous DNA damage which stimulates the p53 response in HSCs, which then accelerates their aging, resulting in a myeloid lineage biased output. Overall design: Lin-Sca1+cKit+ cells from WT, Aldh2 knock-outs, Fancd2 knock-outs, p53 knock-outs, Aldh2 & Fancd2 double knock-outs, Aldh2 & Fancd2 & p53 triple knock-outs
Sample: RBG25050_WT
SAMN29957756 • SRS14298400 • All experiments • All runs
Organism: Mus musculus
Library:
Name: GSM6387759
Instrument: Illumina HiSeq 2500
Strategy: RNA-Seq
Source: TRANSCRIPTOMIC
Selection: cDNA
Layout: SINGLE
Construction protocol: To harvest mouse bone marrow cells, spine, femurs, tibiae and pelvic bones were crushed with a pestle and mortar in 3 mL PBS + 2% FBS. Further 3 mL PBS + 2% FCS were used to wash the bones and the resulting cell suspension was filtered through a 0.75 uM filter. Cells were pelleted and resuspended in 3 mL PBS + 2% FBS. Red cell lysis was performed using cold ammonium chloride (StemCell Technologies cat. no 07800). PBS 2% FCS was added to dilute the red cell lysis buffer during subsequent centrifugation at 4 oC. For lineage depletion, EasySep™ Mouse Hematopoietic Progenitor Cell Enrichment Kit from StemCell Technologies (cat no. 19816A) was used according to the manufacturer's instructions but avoiding the use of rat serum. Samples were transferred into 5 ml polystyrene (352058) FACS tubes and incubated with 10 µl/ml EasySep mouse hematopoietic progenitor cell isolation cocktail labelled with biotin. 40 µl/ml of EasySep™ Streptavidin RapidSpheres were added and allowed to bind on ice for 10 minutes. The samples were subsequently diluted to 2.5 ml using PBS + 2% FBS and placed in the EasyStep magnet (StemCell Technologies cat no. 18000) for 3 minutes at room temperature. After incubation, samples were transferred into new tubes, spun down, and resuspended in 100 ul PBS + 2% FCS. For antibody staining, a master mix was prepared as indicated in table 2 and cell suspensions were incubated on ice, in the dark for 30 minutes. After staining, cells were washed, pelleted, and resuspended in 100 ul PBS + 2% FCS. Were necessary, streptavidin conjugated antibody was added in a second step. Samples were pelleted and resuspended to a final volume of 500 ul PBS + 2% FCS. We used single colour, unstained, and full panel controls that were made using pooled BM cells from all mice before lineage depletion. Primary single cells (LSK cells – Lin-Sca1+ckit+) were FACS index sorted into lysis buffer (0.2% Triton X-100 (Sigma), RNase inhibitor (SUPERase, Thermofisher), and nuclease-free water (Thermo Fisher)). scRNA sequencing was performed according to the Smart-Seq2 protocol. Libraries were prepared using the Illumina nextera XT DNA preparation kit and sequenced on the Illumina Hi-Seq 2500.
Runs: 1 run, 578,301 spots, 28.9M bases, 11.2Mb
Run# of Spots# of BasesSizePublished
SRR20642035578,30128.9M11.2Mb2023-05-24

ID:
23394619

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