This SuperSeries is composed of the SubSeries listed below.
Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase.
Sex, Age, Specimen part, Treatment
View SamplesImmune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-B is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-B activity may contribute to the mild pro-inflammatory state of aging.
Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase.
Sex, Age, Specimen part, Treatment
View SamplesImmune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-B is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-B activity may contribute to the mild pro-inflammatory state of aging.
Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase.
Sex, Age, Specimen part, Treatment
View SamplesImmune impairment and high circulating level of pro-inflammatory cytokines are landmarks of human aging. However, the molecular basis of immune dysregulation and the source of inflammatory markers remain unclear. Here we demonstrate that in the absence of overt cell stimulation, gene expression mediated by the transcription factor NF-B is higher in purified and rested human CD4+ T lymphocytes from older compared to younger individuals. This increase of NF-B -associated transcription includes transcripts for pro-inflammatory cytokines such as IL-1 and chemokines such as CCL2 and CXCL10. We demonstrate that NF-B up-regulation is cell-intrinsic and mediated in part by phosphatidylinositol 3-kinase (PI3K) activity induced in response to metabolic activity, which can be moderated by rapamycin treatment. Our observations provide direct evidence that dysregulated basal NF-B activity may contribute to the mild pro-inflammatory state of aging.
Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase.
Sex, Age, Specimen part, Treatment
View SamplesCirculating extracellular RNAs (exRNAs) are potential biomarkers of disease. We thus hypothesized that age-related changes in exRNAs can identify age-related processes. We profiled both large and small RNAs in human serum to investigate changes associated with normal aging. exRNA was sequenced in 13 young (30-32 yrs.) and 10 old (80-85 yrs.) African American women to identify all RNA transcripts present in serum. We identified age-related differences in several RNA biotypes, including mitochondrial transfer RNAs, mitochondrial ribosomal RNA, and unprocessed pseudogenes. Age-related differences in unique RNA transcripts were further validated in an expanded cohort. Pathway analysis revealed that EIF2 signaling, oxidative phosphorylation, and mitochondrial dysfunction were among the top pathways shared between young and old. Protein interaction networks revealed distinct clusters of functionally-related protein-coding genes in both age-groups. These data provide timely and relevant insight into the exRNA repertoire in serum and its change with aging. Overall design: Profiling of extracellular RNA (exRNA) from human serum in 13 young (30.9 ± 0.60 yrs) and 10 old (81.8 ± 1.87 yrs) individuals.
Extracellular RNA profiles with human age.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Hypomethylation of the IL17RC promoter associates with age-related macular degeneration.
Age, Specimen part, Disease, Cell line
View SamplesAge related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. While recent studies have demonstrated strong genetic associations of single nucleotide polymorphisms within a number of genes and AMD, other modes of regulation are also likely to play a role in its aetiology. We undertook DNA methylation microarray analysis on monozygotic and dizygotic twins who were discordant for AMD and identified methylated IL17RC promoters as being present only in non-AMD control individuals rather than in AMD patients. We validated this finding of a significantly decreased level of methylation on the IL17RC promoter in AMD siblings as well as in a case control study involving 202 genetically unrelated AMD patients and 96 controls (95% CI, 0.03-0.17, P=3.1x10-8). Further, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and mRNA in peripheral blood as well as in the retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis.
Hypomethylation of the IL17RC promoter associates with age-related macular degeneration.
Specimen part, Cell line
View SamplesBackground
Hypomethylation of the IL17RC promoter associates with age-related macular degeneration.
Age, Specimen part
View SamplesEML1 and EML3 were previously shown to be histone readers involved in plant-pathogen interactions. To learn more about the developmental function of EML1 and EML3, we generated eml1 eml3 double mutant and showed that it had specific seed developmental phenotypes, including a capability to develop seed without fertilization. Next, we analyzed the mRNA expression of genes in the eml1 eml3 double mutant and compared it to its wild type. Differentially expressed (DE) genes in the mutant were identified and compared with DE of the mutants known to be involved in regulating seed development and in fertilization-independent endosperm development. Our results suggest that some targets are shared between EML histone readers and known regulators of seed development, such as MEA. Auxin response seems to be affected in both types of mutants. However, unlike MEA, EML proteins regulate auxin responsive genes not only in the endosperm, but also in the embryo. This capability makes EML proteins very good candidates for engineering apomictic seeds. Overall design: 3 eml1,eml3 double mutant samples and 3 WT samples
Arabidopsis EMSY-like (EML) histone readers are necessary for post-fertilization seed development, but prevent fertilization-independent seed formation.
Specimen part, Subject
View SamplesResistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM). We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma. Overall design: We examine 1) gene expression of MM cells in response to PI and 2)alternative splicing in response to PI and comparator chemotherapeutic compound. We further investigate splice factor mechanism in MM cells, by examining alternative splicing in MM with overexpression of wild type and mutant splice factor, SRSF1
Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma.
Cell line, Subject, Compound, Time
View Samples