ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE138544 | GEO | 2020/08/03
REPOSITORIES: GEO
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Project description:Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and increased risk for myelodysplasia and leukemia. Deficient DNA repair contributes to the decline in HSC self-renewal capacity during aging and it remains unclear whether extrinsic signals can rejuvenate aged HSCs. Here, we demonstrate that augmentation of non-homologous end-joining (NHEJ) DNA repair in aged HSCs via treatment with epidermal growth factor (EGF) rejuvenates HSC function. Seven day culture of BM CD34-ckit+sca-1+lin- (34-KSL) HSCs from aged C57BL/6 mice with EGF suppressed myeloid skewing and increased production of multipotent CFU-granulocyte, erythroid, monocyte and megakaryocyte (CFU-GEMM) colonies. Aged, EGF-treated HSCs displayed increased donor multilineage engraftment in primary competitively transplanted mice and in secondary mice compared to mice transplanted with aged, control HSCs. Donor cell engraftment within the bone marrow (BM) KSL and SLAM+KSL HSC population was > 2-fold increased in mice transplanted with aged, EGF-treated HSCs. Systemic administration of EGF to aged mice for 6 weeks also increased long term – HSC self-renewal capacity as measured by increased donor bone marrow (BM) competitive repopulation in primary and secondary transplanted mice. Conversely, deletion of EGFR in Scl/Tal1+ hematopoietic cells was associated with increased myeloid skewing and depletion of LT-HSCs in middle aged mice. Mechanistically, EGF treatment decreased DNA damage in aged HSCs through activation of DNA PK-cs, Artemis and NHEJ repair. Inhibition of DNA PK-cs blocked EGF-mediated restoration of multipotent differentiation and suppression of myeloid skewing in aged HSCs, suggesting that the restoration of hematopoietic potential in aged HSCs is dependent on EGF-mediated activation of DNA PK-cs. EGF treatment also converted the transcriptome of aged HSCs from enrichment for genes involved in cell death and survival to genes involved in HSC generation and identity. These data suggest that extrinsic activation of EGFR signaling can restore key functional capacities in aged HSCs.
2024-04-01 | GSE252293 | GEO
Project description:ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals
| PRJNA576353 | ENA
Project description:Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and increased risk for myelodysplasia and leukemia. Deficient DNA repair contributes to the decline in HSC self-renewal capacity during aging and it remains unclear whether extrinsic signals can rejuvenate aged HSCs. Here, we demonstrate that augmentation of non-homologous end-joining (NHEJ) DNA repair in aged HSCs via treatment with epidermal growth factor (EGF) rejuvenates HSC function. Seven day culture of BM CD34-ckit+sca-1+lin- (34-KSL) HSCs from aged C57BL/6 mice with EGF suppressed myeloid skewing and increased production of multipotent CFU-granulocyte, erythroid, monocyte and megakaryocyte (CFU-GEMM) colonies. Aged, EGF-treated HSCs displayed increased donor multilineage engraftment in primary competitively transplanted mice and in secondary mice compared to mice transplanted with aged, control HSCs. Donor cell engraftment within the bone marrow (BM) KSL and SLAM+KSL HSC population was > 2-fold increased in mice transplanted with aged, EGF-treated HSCs. Systemic administration of EGF to aged mice for 6 weeks also increased long term – HSC self-renewal capacity as measured by increased donor bone marrow (BM) competitive repopulation in primary and secondary transplanted mice. Conversely, deletion of EGFR in Scl/Tal1+ hematopoietic cells was associated with increased myeloid skewing and depletion of LT-HSCs in middle aged mice. Mechanistically, EGF treatment decreased DNA damage in aged HSCs through activation of DNA PK-cs, Artemis and NHEJ repair. Inhibition of DNA PK-cs blocked EGF-mediated restoration of multipotent differentiation and suppression of myeloid skewing in aged HSCs, suggesting that the restoration of hematopoietic potential in aged HSCs is dependent on EGF-mediated activation of DNA PK-cs. EGF treatment also converted the transcriptome of aged HSCs from enrichment for genes involved in cell death and survival to genes involved in HSC generation and identity. These data suggest that extrinsic activation of EGFR signaling can restore key functional capacities in aged HSCs.
2024-07-01 | GSE266959 | GEO
Project description:BackgroundImmunologic aging leads to immune dysfunction, significantly reducing the quality of life of the elderly. Aged-related defects in early hematopoiesis result in reduced lymphoid cell development, functionally defective mature immune cells, and poor protective responses to vaccines and pathogens. Despite considerable progress understanding the underlying causes of decreased immunity in the elderly, the mechanisms by which these occur are still poorly understood. The DNA-binding protein ARID3a is expressed in a subset of human hematopoietic progenitors. Inhibition of ARID3a in bulk human cord blood CD34+ hematopoietic progenitors led to developmental skewing toward myeloid lineage at the expense of lymphoid lineage cells in vitro. Effects of ARID3a expression in adult-derived hematopoietic stem cells (HSCs) have not been analyzed, nor has ARID3a expression been assessed in relationship to age. We hypothesized that decreases in ARID3a could explain some of the defects observed in aging.ResultsOur data reveal decreased frequencies of ARID3a-expressing peripheral blood HSCs from aged healthy individuals compared with young donor HSCs. Inhibition of ARID3a in young donor-derived HSCs limits B lineage potential, suggesting a role for ARID3a in B lymphopoiesis in bone marrow-derived HSCs. Increasing ARID3a levels of HSCs from aged donors in vitro alters B lineage development and maturation. Finally, single cell analyses of ARID3a-expressing HSCs from young versus aged donors identify a number of differentially expressed genes in aged ARID3A-expressing cells versus young ARID3A-expressing HSCs, as well as between ARID3A-expressing and non-expressing cells in both young and aged donor HSCs.ConclusionsThese data suggest that ARID3a-expressing HSCs from aged individuals differ at both molecular and functional levels compared to ARID3a-expressing HSCs from young individuals.
| S-EPMC7469297 | biostudies-literature
Project description:Phenotypic and functional changes seen in the aged adaptive immune system are primarily driven by aging of hematopoietic stem cells (HSCs), pharmacological rejuvenated aged HSCs were able to reconstituted a youthful immune system
2018-06-12 | GSE107007 | GEO
Project description:In order to determine proteins interacting with ARID3A in the ML-DS cell line CMK, we performed CoIP of endogenous ARID3A followed by LC-MS/MS
2023-03-11 | PXD025027 | Pride
Project description:During X chromosome inactivation (XCI), the inactive X chromosome (Xi) is recruited to the nuclear lamina at the periphery of the nucleus. Beside X chromosome (X chr) reactivation resulting in a highly penetrant aging-like hematopoietic malignancy, little is known about XCI in aged hematopoietic stem cells (HSCs) . Here, we demonstrate that LaminA/C defines a distinct repressive nuclear compartment for XCI in young HSCs, and its reduction in aged HSCs correlates with an impairment in the overall control of XCI. Integrated omics analyses reveal higher variation in gene expression, global hypomethylation and significantly increased chromatin accessibility on the X chr in aged HSCs. In summary, our data support the role of LaminA/C in the establishment of a special repressive compartment for XCI in HSCs, which is impaired upon aging.
2021-04-07 | GSE167214 | GEO
Project description:Methyl-seq data was obtained from total peripheral blood mononuclear cells of two patients with systemic lupus erythematosus who were characterized as having>2 standard deviations more ARID3a-expressing B lymphocytes than healthy controls. Similarly, methyl-seq data was also obtained from two SLE patient samples with normal (low) numbers of ARID3-expressing B lymphocytes. Our previous studies showed that increased ARID3a expression in B lymphocytes was associated increased disease activity. Data were generated on an Illumina Hiseq 2000 with paired-end 100bp reads and quality control metrics were assessed with Picard tools. Methylation profiles of genomic DNA from four SLE patient PBMC samples, two with high numbers of ARID3a expressing B cells (ARID3aH) versus two with normal numbers of ARID3a+ B cells (ARID3aN), were generated on an Illumina Hiseq 2000 with paired-end 100bp reads.
2016-08-19 | E-GEOD-84965 | biostudies-arrayexpress
Project description:Purpose: Compare the transcriptome of hematopoietic stem cells (HSCs) that were aged in old and young niches Methods: barcoded GFP+ HSCs were FACS-sorted from a) three recipient mice 15 months post transplantation, and b) six serial transplantation recipient mice 5 months after the 8th transplantation, then subjected to processed using the Chromium Single-cell 3′ v2 Library Kit (10× Genomics, Pleasanton, CA) following the manufacturer’s instructions Results: we obtained transcriptomes of about 12k HSCs aged in young niche, and about 10k HSCs aged in old niche, with the average sequencing depth at close to 50k reads per cell Conclusions: we identified striking differences in gene expression profiles 1) between HSCs aged in young niches from mice with early aging and from mice with delayed aging, and 2) between HSCs aged in old niches and young niches when mice exhibited hematopoietic aging phenotype
2021-01-01 | GSE154772 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Hematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Here, we performed an integrated analysis of transcriptome and chromatin accessibility of aged HSCs and downstream progenitors. Alterations in chromatin accessibility preferentially took place in HSCs with aging, which gradually resolved with differentiation. Differentially open accessible regions (open DARs) in aged HSCs showed enrichment of binding motifs of the STAT, ATF, and CNC family transcription factors that are activated in response to external stresses, and most of them comprised active, primed , and inactive enhancers. Genes linked to open DARs showed significantly higher levels of basal expression and their expression reached significantly higher peaks after cytokine stimulation in aged HSCs than in young HSCs, suggesting that open DARs contribute to augmented transcriptional responses under stress conditions. These results indicate that the ongoing and/or history of exposure to external stresses is epigenetically inscribed in HSCs to augment their responses to external stimuli.
2020-12-05 | GSE162662 | GEO