Transcriptional alterations of human HSCs in aging and MDS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA550975 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9600850.fastq.gz | Fastqsanger.gz | |||
| SRR9600860.fastq.gz | Fastqsanger.gz | |||
| SRR9600870.fastq.gz | Fastqsanger.gz | |||
| SRR9600880.fastq.gz | Fastqsanger.gz | |||
| SRR9600851.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. To determine the molecular mechanism of severe cytopenia in NHD13+ Tg mice, we purified Lin-Sca-1+c-Kit+CD34-Flt3-CD150+ HSCs from WT and NHD13+Tg mice at 4 month of age and perform the RNA-seq analysis. Methods: Trizol was used to extract RNA from FACS sorted CD150+CD34–Flt3–LSK viable cells. Total RNA was used for quality controls and for normalization of starting material. cDNA-libraries were generated with 10 ng of total RNA using the SMARTer Ultra Low RNA Kit for Illumina Sequencing according to the manufacturer’s indications. Sequencing was done using the Illumina Next-Gen Sequencing HiSeq platform with 30-45 million 75bp, paired-end reads. Results: We found 597 genes with significantly differential expression in NHD13+ HSCs, compared to WT controls (p<0.001). The expression of NUP98-HOXD13 up-regulated the expression of HOX genes, including Hoxa3, Hoxa5, Hoxa7, Hoxa9, Hoxb6, Hoxc5, Hoxc6, Hoxc8, Hoxc9 and Hoxd3, the important myeloid transcription factor Pbx3, cell cycle regulators, Cdk6 and Cdc25C, as well as the transcripts encoding the Ly6d surface membrane protein. We then performed pathway analyses, which showed that DNA duplication, DNA damage response and cell cycle-related genes, were more highly expressed in NHD13+ HSCs than WT HSCs, while multiple metabolic process-related gene pathways were downregulated. Conclusions: Our analyses demonstrate that the gene expression signature defined in murine NHD13+ MDS HSCs displays robust similarities with the gene expression profiles of human MDS cells, strongly suggesting that this murine MDS model can be used to accurately model human MDS.
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Project description:Leptin receptor (LEPR) identifies a subpopulation of hematopoietic stem cells (HSCs) with high repopulating potential. In this study, we demonstrated that LEPR-expressing HSCs while exhibiting significantly higher engrafting potential and self-renewing capacity in young mice showed early age-associated decline in these functions as compared to the LEPR- HSCs. LEPR+ HSCs have transcriptomic profiles significantly different from LEPR- HSCs in young mouse bone marrow, but middle-aged HSCs do not have distinct transcriptomic profiles based on LEPR status. The age-related phenotypes were associated with a proinflammatory transcriptomic profile at baseline in young LEPR+ HSCs, which was further exacerbated by age. In contrast, LEPR- HSCs did not show age-associated functional impairment at the ages tested. This suggested that subsets of HSCs are susceptible to age-related decline in function at varying ages and that LEPR+ HSCs are a potential target for early cellular therapeutic interventions in delaying the detrimental effects of aging in hematopoiesis.
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Project description:Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis with increased incidence in elderly individuals. Genetic alterations do not fully explain the molecular pathogenesis of the disease, indicating that other types of lesions may play a role in its development. In this work, we analyzed the transcriptional lesions of human HSCs, demonstrating how aging and MDS are characterized by a complex transcriptional rewiring that manifests as diverse linear and non-linear transcriptional dynamisms. While aging-associated lesions seemed to predispose elderly HSCs to myeloid transformation, disease-specific alterations may be involved in triggering MDS development. Among MDS-specific lesions, we detected the overexpression of the transcription factor (TF) DDIT3. Exogenous upregulation of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis, with an accumulation of cells in early stages of erythroid differentiation, as determined by single-cell RNA-sequencing. Increased DDIT3 expression was associated with downregulation of transcription factors required for normal erythropoiesis, such as KLF1, TAL1 or SOX6, and with a failure in the activation of their erythroid transcriptional programs. Finally, DDIT3 knockdown in CD34+ cells from MDS patients was able to restore erythropoiesis, as demonstrated by immunophenotypic and transcriptional profiling. These results demonstrate that DDIT3 may be a driver of MDS transformation, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing these patients.
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Project description:Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis with increased incidence in elderly individuals. Genetic alterations do not fully explain the molecular pathogenesis of the disease, indicating that other types of lesions may play a role in its development. In this work, we analyzed the transcriptional lesions of human HSCs, demonstrating how aging and MDS are characterized by a complex transcriptional rewiring that manifests as diverse linear and non-linear transcriptional dynamisms. While aging-associated lesions seemed to predispose elderly HSCs to myeloid transformation, disease-specific alterations may be involved in triggering MDS development. Among MDS-specific lesions, we detected the overexpression of the transcription factor (TF) DDIT3. Exogenous upregulation of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis, with an accumulation of cells in early stages of erythroid differentiation, as determined by single-cell RNA-sequencing. Increased DDIT3 expression was associated with downregulation of transcription factors required for normal erythropoiesis, such as KLF1, TAL1 or SOX6, and with a failure in the activation of their erythroid transcriptional programs. Finally, DDIT3 knockdown in CD34+ cells from MDS patients was able to restore erythropoiesis, as demonstrated by immunophenotypic and transcriptional profiling. These results demonstrate that DDIT3 may be a driver of MDS transformation, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing these patients.
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