The chromatin accessibility signature of human immune aging stems from CD8+ T cells
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ABSTRACT:
PROVIDER: EGAS00001002605 | EGA |
REPOSITORIES: EGA
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Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
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Project description:Nucleosomes are flanked by histone H1’s which bind linker DNA and aid chromatin compaction. The specific role of linker histone has remained elusive due to complex compensatory mechanisms among H1 variants. H1.4 ablation resulted in robust changes in nascent transcription and gene expression, with critical pathways upregulated (RAR, TNF-α/NF-κB) and extracellular matrix and collagen genes repressed. Alternations to chromatin accessibility intersected extragenic and intronic regions, overlapped sites of known enhancer chromatin, and were of enhancer-size. These sites exhibited concomitant and concordant changes to epigenetic marks (H3K27ac/H3K4me1). Sites which gained accessibility contained binding motifs for basal factors (TBP, SRF), localized to polycomb, heterochromatin and quiescent/low chromatin and gained active RNA transcription in ΔH1.4 cells. However, the AP-1 motif was enriched at sites which lost accessibility, consistent with the gene expression changes. This places histone H1.4 as a hitherto underappreciated regulator of transcriptional response patterns and a dynamic member of regulatory chromatin.
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Project description:To identify conserved TNFα-induced changes in chromatin-accessibility in mammals, we performed ATAC-seq in primary vascular endothelial cells (ECs) isolated from the aortas of human (HAEC), mouse (MAEC) and cow (BAEC), before and after TNFα. We overlay our data with multi-species NF-κB binding data and identify multiple modes of NF-κB-chromatin interactions that are conserved during mammalian TNFα response. Our cross-species approach identifies conserved changes in chromatin-accessibility at NF-κB binding sites that are disease-relevant and essential during mammalian acute inflammation.
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Project description:To test the chromatin accessibility of different immune cell subsets, we isolated CD4+T cells, CD8+T cells, CD19+B cells and CD14+ monocytes from human PBMCs and performed ATAC assay.
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Project description:Over activation of NF-κB has close relationship with hepatitis and hepatocellular carcinoma (HCC). In this study, by manipulating NF-κB activity with its recognized activator TNFα and using ChIP-seq and RNA-seq techniques, we identified 699 NF-κB direct target genes (DTGs) in a widely used HCC cell line, HepG2, including 399 activated and 300 repressed genes. In these NF-κB DTGs, 216 genes (126 activated and 90 repressed genes) are among the current HCC gene signature. Functional annotation revealed that NF-κB DTGs in HepG2 cell are mainly related with many typical NF-κB-related biological processes, such as immune system process, response to stress, response to stimulus, defense response and signaling pathways of NF-kappa B. Some NF-κB DTGs are also involved in Hepatitis C and B pathways. The NF-κB DTGs were further confirmed by detecting the NF-κB binding and expression of 14 genes with ChIP-PCR and RT-PCR.
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Project description:Over activation of NF-κB has close relationship with hepatitis and hepatocellular carcinoma (HCC). In this study, by manipulating NF-κB activity with its recognized activator TNFα and using ChIP-seq and RNA-seq techniques, we identified 699 NF-κB direct target genes (DTGs) in a widely used HCC cell line, HepG2, including 399 activated and 300 repressed genes. In these NF-κB DTGs, 216 genes (126 activated and 90 repressed genes) are among the current HCC gene signature. Functional annotation revealed that NF-κB DTGs in HepG2 cell are mainly related with many typical NF-κB-related biological processes, such as immune system process, response to stress, response to stimulus, defense response and signaling pathways of NF-kappa B. Some NF-κB DTGs are also involved in Hepatitis C and B pathways. The NF-κB DTGs were further confirmed by detecting the NF-κB binding and expression of 14 genes with ChIP-PCR and RT-PCR.
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Project description:The establishment of highly accurate aging clocks based on DNA methylation highlighted the strong link between epigenetic alterations and aging. However, connecting methylation clocks to physiological changes is not straightforward. Transcriptomics and proteomics clocks on the other hand are directly connected to cellular function, yet they do not allow us to understand underlying epigenetic mechanisms. We hypothesize that chromatin accessibility, a readout that integrates many epigenetic mechanisms, may bridge epigenetic changes with their downstream effects in aging. To demonstrate that chromatin accessibility can predict age, we generated chromatin accessibility profiles from peripheral blood mononuclear cells (PBMCs) of 157 human donors, aged 20 to 74 and used them to construct a novel aging clock. Our clock predicted age with a root mean squared error of 7.69 years, a median absolute error of 5.69 years and a correlation of 0.83. Moreover, by comparing our chromatin accessibility data to matched transcriptomic profiles, we show that the genomic sites selected by our clock drive changes in transcription during aging. This chromatin accessibility clock could therefore be used to better understand the mechanisms driving the process of aging and evaluate anti-aging interventions.
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Project description:The establishment of highly accurate aging clocks based on DNA methylation highlighted the strong link between epigenetic alterations and aging. However, connecting methylation clocks to physiological changes is not straightforward. Transcriptomics and proteomics clocks on the other hand are directly connected to cellular function, yet they do not allow us to understand underlying epigenetic mechanisms. We hypothesize that chromatin accessibility, a readout that integrates many epigenetic mechanisms, may bridge epigenetic changes with their downstream effects in aging. To demonstrate that chromatin accessibility can predict age, we generated chromatin accessibility profiles from peripheral blood mononuclear cells (PBMCs) of 157 human donors, aged 20 to 74 and used them to construct a novel aging clock. Our clock predicted age with a root mean squared error of 7.69 years, a median absolute error of 5.69 years and a correlation of 0.83. Moreover, by comparing our chromatin accessibility data to matched transcriptomic profiles, we show that the genomic sites selected by our clock drive changes in transcription during aging. This chromatin accessibility clock could therefore be used to better understand the mechanisms driving the process of aging and evaluate anti-aging interventions.
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Project description:The overriding objective of this application is to seek funding for the development of a crossectional profile of immune phenotype of over 600 normal subjects between the ages of 50 and 90. As a consequence, we will infer changes in immune phenotype of normal subjects as they age. These immune phenotypic data, as well as standard laboratory tests and evaluations of questionnaires, will be used to generate a large and comprehensive database of demographic and biological information. The proposal utilizes the strengths of the Stanford Human Immune Monitoring Core (HIMC) and the unique expertise in basic immunology, immune monitoring, the development of patient registries, biostatistics and bioinformatics at Stanford. The dataset will comprise a crossectional analysis of the local San Francisco Peninsula general population between the ages of 50 and 90 (representing equal gender and representative ethnic population, and equal distribution by decade of life). The registry will contain demographic data, race/ethnicity, prescribed medications, over the counter medications, vitamins, alternative therapies, physical function questionnaire, alternative contact person, and HIPPA release. Fasting blood will be obtained for immune phenotyping. The immune profile will contain the results of both conventional and novel immune profiling assays to develop the normative immune profile of aging (using PBMC subset analysis, cytokines, and activation induced signaling of PBMCs for phosphoepitope and gene expression analyses). Data from these analyses will be useful in identifying biomarkers of the normal immune profile associated with aging as well as correlation with phenotypic aspects of aging such as sarcopenia and disability The immune profile (as well as normal blood chemistries and demographic data) of these subjects will be made available to serve as the basis for future longitudinal study of change in the immune profile over time in association with the development of co-morbidities associated with aging. in the PBMC gene expression, 120 samples were analyzed (no replicates), containing patients and controls.
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Project description:The overriding objective of this application is to seek funding for the development of a crossectional profile of immune phenotype of over 600 normal subjects between the ages of 50 and 90. As a consequence, we will infer changes in immune phenotype of normal subjects as they age. These immune phenotypic data, as well as standard laboratory tests and evaluations of questionnaires, will be used to generate a large and comprehensive database of demographic and biological information. The proposal utilizes the strengths of the Stanford Human Immune Monitoring Core (HIMC) and the unique expertise in basic immunology, immune monitoring, the development of patient registries, biostatistics and bioinformatics at Stanford. The dataset will comprise a crossectional analysis of the local San Francisco Peninsula general population between the ages of 50 and 90 (representing equal gender and representative ethnic population, and equal distribution by decade of life). The registry will contain demographic data, race/ethnicity, prescribed medications, over the counter medications, vitamins, alternative therapies, physical function questionnaire, alternative contact person, and HIPPA release. Fasting blood will be obtained for immune phenotyping. The immune profile will contain the results of both conventional and novel immune profiling assays to develop the normative immune profile of aging (using PBMC subset analysis, cytokines, and activation induced signaling of PBMCs for phosphoepitope and gene expression analyses). Data from these analyses will be useful in identifying biomarkers of the normal immune profile associated with aging as well as correlation with phenotypic aspects of aging such as sarcopenia and disability The immune profile (as well as normal blood chemistries and demographic data) of these subjects will be made available to serve as the basis for future longitudinal study of change in the immune profile over time in association with the development of co-morbidities associated with aging. in the PBMC gene expression, 120 samples were analyzed (no replicates), containing patients and controls.
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