Single-cell profiling of hematopoietic cells in VEXAS syndrome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA803179 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17873100.fastq.gz | Fastqsanger.gz | |||
| SRR17873200.fastq.gz | Fastqsanger.gz | |||
| SRR17873300.fastq.gz | Fastqsanger.gz | |||
| SRR17873400_1.fastq.gz | Fastqsanger.gz | |||
| SRR17873400_2.fastq.gz | Fastqsanger.gz |
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Project description:Background and methods: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has been recently recognized as an adult-onset autoinflammatory syndrome due to somatic mutations affecting Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) gene. Following-up studies have been mostly limited to case reports; transcriptome of especially hematopoiesis in VEXAS syndrome has not been well characterized. Results: We performed whole transcriptome sequencing of single bone marrow cells (BMMNCs) and enriched Lineage-CD34+ hematopoietic stem and progenitor cells (HSPCs) from nine patients included in the original VEXAS cohort. We profiled inflammation and hematopoietic differentiation in these patients, and found activation of inflammatory gene programs particularly in marrow myeloid cells; HSPCs showed a preferred myeloid dominance. Patients had profound abnormalities in gene expression involved in pathways of inflammation, cell cycling and activation, and protein synthesis. We defined single bone marrow cells with expressed UBA1 mutations, and characterized gene expression of mutant myeloid cells as compared to that of wild-type, and observed upregulation of inflammatory pathways and immune activation; increased cell cycling might contribute to clonal dominance of UBA1 mutant cells. We were also able to profile other somatic mutations (DNMT3A) in two patients who had concurrent DNMT3A mutations at a high frequency. With coupled single cell T/B-cell receptor (TCR/BCR) sequencing, we characterized TCR and BCR repertoire in four patients, two of whom had B cell lymphocytosis. Cell-cell interaction analysis revealed enhanced interactions of myeloid cells with HSPCs, and interferons interaction with their receptors were frequent. We also performed bulk RNA sequencing of several leukemic cell lines with UBA1 knockdown, and observed upregulation of inflammatory pathways in these UBA1 knockdown cell lines. Conclusion: Our study discloses transcriptome signatures of hematopoietic cells in VEXAS syndrome, providing a broad perspective into potential pathogenesis of this novel disease.
2023-07-18 | GSE196052 | GEO
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Project description:Large deletions in mitochondrial DNA (mtDNA) have been linked to a variety of clinical pathologies, including somatic emergence in congenital disorders such as Pearson Syndrome (MIM:557000), a mitochondrial disease characterized by sideroblastic anemia and exocrine pancreas dysfunction. Here, we develop a multi-omics approach to quantify mtDNA deletion heteroplasmy and cell state features in thousands of single cells. By profiling primary hematopoietic cells from three patients with Pearson Syndrome, we resolve the interdependence between pathogenic mtDNA heteroplasmy and cell lineage, including purifying selection against mtDNA deletions in effector-memory CD8 T-cell populations. We further observe widespread Pearson-specific transcriptomic changes in peripheral blood mononuclear cells. Additionally, single-cell analyses of in vivo and in vitro cultured bone marrow mononuclear cells reveal multi-faceted clonal dynamics and purifying selection in a patient with both Pearson Syndrome and Myelodysplastic Syndrome (MDS). Our results identify specific molecular perturbations underlying Pearson Syndrome and more generally provide a powerful framework to utilize multi-omics in the study of evolution in disease within single cells.
2023-04-14 | GSE173935 | GEO
Project description:Large deletions in mitochondrial DNA (mtDNA) have been linked to a variety of clinical pathologies, including somatic emergence in congenital disorders such as Pearson Syndrome (MIM:557000), a mitochondrial disease characterized by sideroblastic anemia and exocrine pancreas dysfunction. Here, we develop a multi-omics approach to quantify mtDNA deletion heteroplasmy and cell state features in thousands of single cells. By profiling primary hematopoietic cells from three patients with Pearson Syndrome, we resolve the interdependence between pathogenic mtDNA heteroplasmy and cell lineage, including purifying selection against mtDNA deletions in effector-memory CD8 T-cell populations. We further observe widespread Pearson-specific transcriptomic changes in peripheral blood mononuclear cells. Additionally, single-cell analyses of in vivo and in vitro cultured bone marrow mononuclear cells reveal multi-faceted clonal dynamics and purifying selection in a patient with both Pearson Syndrome and Myelodysplastic Syndrome (MDS). Our results identify specific molecular perturbations underlying Pearson Syndrome and more generally provide a powerful framework to utilize multi-omics in the study of evolution in disease within single cells.
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Project description:Large deletions in mitochondrial DNA (mtDNA) have been linked to a variety of clinical pathologies, including somatic emergence in congenital disorders such as Pearson Syndrome (MIM:557000), a mitochondrial disease characterized by sideroblastic anemia and exocrine pancreas dysfunction. Here, we develop a multi-omics approach to quantify mtDNA deletion heteroplasmy and cell state features in thousands of single cells. By profiling primary hematopoietic cells from three patients with Pearson Syndrome, we resolve the interdependence between pathogenic mtDNA heteroplasmy and cell lineage, including purifying selection against mtDNA deletions in effector-memory CD8 T-cell populations. We further observe widespread Pearson-specific transcriptomic changes in peripheral blood mononuclear cells. Additionally, single-cell analyses of in vivo and in vitro cultured bone marrow mononuclear cells reveal multi-faceted clonal dynamics and purifying selection in a patient with both Pearson Syndrome and Myelodysplastic Syndrome (MDS). Our results identify specific molecular perturbations underlying Pearson Syndrome and more generally provide a powerful framework to utilize multi-omics in the study of evolution in disease within single cells.
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Project description:Large deletions in mitochondrial DNA (mtDNA) have been linked to a variety of clinical pathologies, including somatic emergence in congenital disorders such as Pearson Syndrome (MIM:557000), a mitochondrial disease characterized by sideroblastic anemia and exocrine pancreas dysfunction. Here, we develop a multi-omics approach to quantify mtDNA deletion heteroplasmy and cell state features in thousands of single cells. By profiling primary hematopoietic cells from three patients with Pearson Syndrome, we resolve the interdependence between pathogenic mtDNA heteroplasmy and cell lineage, including purifying selection against mtDNA deletions in effector-memory CD8 T-cell populations. We further observe widespread Pearson-specific transcriptomic changes in peripheral blood mononuclear cells. Additionally, single-cell analyses of in vivo and in vitro cultured bone marrow mononuclear cells reveal multi-faceted clonal dynamics and purifying selection in a patient with both Pearson Syndrome and Myelodysplastic Syndrome (MDS). Our results identify specific molecular perturbations underlying Pearson Syndrome and more generally provide a powerful framework to utilize multi-omics in the study of evolution in disease within single cells.
2023-04-14 | GSE173932 | GEO
Project description:Large deletions in mitochondrial DNA (mtDNA) have been linked to a variety of clinical pathologies, including somatic emergence in congenital disorders such as Pearson Syndrome (MIM:557000), a mitochondrial disease characterized by sideroblastic anemia and exocrine pancreas dysfunction. Here, we develop a multi-omics approach to quantify mtDNA deletion heteroplasmy and cell state features in thousands of single cells. By profiling primary hematopoietic cells from three patients with Pearson Syndrome, we resolve the interdependence between pathogenic mtDNA heteroplasmy and cell lineage, including purifying selection against mtDNA deletions in effector-memory CD8 T-cell populations. We further observe widespread Pearson-specific transcriptomic changes in peripheral blood mononuclear cells. Additionally, single-cell analyses of in vivo and in vitro cultured bone marrow mononuclear cells reveal multi-faceted clonal dynamics and purifying selection in a patient with both Pearson Syndrome and Myelodysplastic Syndrome (MDS). Our results identify specific molecular perturbations underlying Pearson Syndrome and more generally provide a powerful framework to utilize multi-omics in the study of evolution in disease within single cells.
2023-04-14 | GSE173931 | GEO
Project description:Large deletions in mitochondrial DNA (mtDNA) have been linked to a variety of clinical pathologies, including somatic emergence in congenital disorders such as Pearson Syndrome (MIM:557000), a mitochondrial disease characterized by sideroblastic anemia and exocrine pancreas dysfunction. Here, we develop a multi-omics approach to quantify mtDNA deletion heteroplasmy and cell state features in thousands of single cells. By profiling primary hematopoietic cells from three patients with Pearson Syndrome, we resolve the interdependence between pathogenic mtDNA heteroplasmy and cell lineage, including purifying selection against mtDNA deletions in effector-memory CD8 T-cell populations. We further observe widespread Pearson-specific transcriptomic changes in peripheral blood mononuclear cells. Additionally, single-cell analyses of in vivo and in vitro cultured bone marrow mononuclear cells reveal multi-faceted clonal dynamics and purifying selection in a patient with both Pearson Syndrome and Myelodysplastic Syndrome (MDS). Our results identify specific molecular perturbations underlying Pearson Syndrome and more generally provide a powerful framework to utilize multi-omics in the study of evolution in disease within single cells.
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Project description:Large deletions in mitochondrial DNA (mtDNA) have been linked to a variety of clinical pathologies, including somatic emergence in congenital disorders such as Pearson Syndrome (MIM:557000), a mitochondrial disease characterized by sideroblastic anemia and exocrine pancreas dysfunction. Here, we develop a multi-omics approach to quantify mtDNA deletion heteroplasmy and cell state features in thousands of single cells. By profiling primary hematopoietic cells from three patients with Pearson Syndrome, we resolve the interdependence between pathogenic mtDNA heteroplasmy and cell lineage, including purifying selection against mtDNA deletions in effector-memory CD8 T-cell populations. We further observe widespread Pearson-specific transcriptomic changes in peripheral blood mononuclear cells. Additionally, single-cell analyses of in vivo and in vitro cultured bone marrow mononuclear cells reveal multi-faceted clonal dynamics and purifying selection in a patient with both Pearson Syndrome and Myelodysplastic Syndrome (MDS). Our results identify specific molecular perturbations underlying Pearson Syndrome and more generally provide a powerful framework to utilize multi-omics in the study of evolution in disease within single cells.
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