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ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals.

ABSTRACT: Background:Immunologic 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. Results:Our 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. Conclusions:These data suggest that ARID3a-expressing HSCs from aged individuals differ at both molecular and functional levels compared to ARID3a-expressing HSCs from young individuals.

SUBMITTER: Ratliff ML

PROVIDER: S-EPMC7469297 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals.

Ratliff Michelle L ML Garton Joshua J James Judith A JA Webb Carol F CF

Immunity & ageing : I & A 20200903

<h4>Background</h4>Immunologic 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 ...[more]

PMID: 32905435

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Project description:BackgroundSingle nucleotide polymorphisms (SNPs) inherited as one of two common haplotypes at the transmembrane protein 106B (TMEM106B) locus are associated with the risk of multiple neurodegenerative diseases, including frontotemporal lobar degeneration with pathological inclusions of TDP-43. Among the associated variants, rs3173615 (encoding p.T185S) is the only coding variant; however, non-coding variants may also contribute to disease risk. It has been reported that the risk haplotype is associated with higher levels of TMEM106B and increased levels of TMEM106B cause cytotoxicity; however, the precise mechanism through which TMEM106B haplotypes contribute to neurodegeneration is unclear.MethodsWe utilized RNA sequencing data derived from temporal cortex (TCX) and cerebellum (CER) from 312 North American Caucasian subjects neuropathologically diagnosed with Alzheimer's disease, progressive supranuclear palsy, pathological aging or normal controls to analyze transcriptome signatures associated with the risk (TT) and protective (SS) TMEM106B haplotypes. In cohorts matched for disease phenotype, we used Analysis of Variance (ANOVA) to identify differentially expressed genes and Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene networks associated with the risk and protective TMEM106B haplotypes.ResultsA total of 110 TCX and 116 CER samples were included in the analyses. When comparing TT to SS carriers, we detected 593 differentially expressed genes in TCX and 7 in CER. Gene co-expression network analyses further showed that in both TCX and CER the SS haplotype was positively correlated with gene networks involved in synaptic transmission, whereas the TT haplotype was positively correlated with gene networks enriched for immune response. Gene expression patterns of 5 cell-type-specific markers revealed significantly reduced expression of the neuronal marker and relative increases in all other cell markers in TT as compared to SS carriers in TCX with a similar but non-significant trend in CER.ConclusionsBy comparing the common TMEM106B risk and protective haplotypes we identified significant and partly conserved transcriptional differences across TCX and CER and striking changes in cell-type composition, especially in TCX. These findings illustrate the profound effect of TMEM106B haplotypes on brain health and highlight the importance to better understand TMEM106B's function and dysfunction in the context of neurodegenerative diseases.

Project description:BackgroundLong-term hematopoietic stem cells (LT-HSCs) migrate from the fetal liver (FL) to the fetal bone marrow (FBM) during development. Various adhesion and chemotactic receptor genes have been implicated in the migration of adult LT-HSCs. However, their role in the migration of fetal LT-HSCs is not clearly understood due, in part, to the rare number of these cells in fetal tissues, which preclude classical gene expression analysis. The aim of this study is to characterize the expression of migration related genes in fetal LT-HSC across different anatomical locations during development.Methodology/principal findingsWe isolated fetal LT-HSC from different developmental stages, as well as different anatomical locations, and performed single-cell multiplex RT-qPCR and flow cytometry analysis of eight molecules involved in adult LT-HSC migration. Our results show that the gene expression of the chemokine receptor Cxcr4 in LT-HSC varies across developmental microenvironments and times, while the cadherin Cdh2 (Ncad) and the calcium receptor Casr show higher gene expression and variability only in FBM at 17.5 days post coitum (dpc). The cadherin Cdh5 (Vecad) maintains high expression variability only during fetal development, while the integrin subunit Itga5 (α5) increases its variability after 14.5 dpc. The integrin subunits Itga4 (α4) and Itgal (Lfa1), as well as the selectin ligand Selplg (Psgl1), did not show differences in their expression in single LT-HSCs irrespective of the developmental times or anatomical microenvironments studied.Conclusions/significanceOur data demonstrate that the expression pattern of phenotypically identical, single LT-HSCs fluctuates as a function of developmental stage and anatomical microenvironment. This is the first exhaustive gene expression comparison of migration-related molecules in fetal tissues across developmental times, enhancing the understanding of LT-HSC migration fate decisions during development.

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Project description:BACKGROUND: A co-ordinated tissue-independent gene expression profile associated with growth is present in rodent models and this is hypothesised to extend to all mammals. Growth in humans has similarities to other mammals but the return to active long bone growth in the pubertal growth spurt is a distinctly human growth event. The aim of this study was to describe gene expression and biological pathways associated with stages of growth in children and to assess tissue-independent expression patterns in relation to human growth. RESULTS: We conducted gene expression analysis on a library of datasets from normal children with age annotation, collated from the NCBI Gene Expression Omnibus (GEO) and EBI Arrayexpress databases. A primary data set was generated using cells of lymphoid origin from normal children; the expression of 688 genes (ANOVA false discovery rate modified p-value, q?<?0.1) was associated with age, and subsets of these genes formed clusters that correlated with the phases of growth--infancy, childhood, puberty and final height. Network analysis on these clusters identified evolutionarily conserved growth pathways (NOTCH, VEGF, TGFB, WNT and glucocorticoid receptor--Hyper-geometric test, q?<?0.05). The greatest degree of network 'connectivity' and hence functional significance was present in infancy (Wilcoxon test, p?<?0.05), which then decreased through to adulthood. These observations were confirmed in a separate validation data set from lymphoid tissue. Similar biological pathways were observed to be associated with development-related gene expression in other tissues (conjunctival epithelia, temporal lobe brain tissue and bone marrow) suggesting the existence of a tissue-independent genetic program for human growth and maturation. CONCLUSIONS: Similar evolutionarily conserved pathways have been associated with gene expression and child growth in multiple tissues. These expression profiles associate with the developmental phases of growth including the return to active long bone growth in puberty, a distinctly human event. These observations also have direct medical relevance to pathological changes that induce disease in children. Taking into account development-dependent gene expression profiles for normal children will be key to the appropriate selection of genes and pathways as potential biomarkers of disease or as drug targets.

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ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals.

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ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals.

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