Ageing-associated proteome and acetylome of Meg3+ HSC
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Lunzhi Dai
PROVIDER: PXD051244 | iProX | Sun Apr 07 00:00:00 BST 2024
REPOSITORIES: iProX
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Project description:Ageing-associated proteome and acetylome of hematopoietic progenitor cells
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Project description:Background: DNA methylation, a component of the epigenome that regulates both single genes and large sections of chromatin, is altered with ageing and is speculated to be one of the molecular mechanisms contributing to the ageing process. In our analysis, we sought to identify ageing-associated methylation changes at single- CpG-site resolution in blood leukocytes and to ensure that the observed changes were not due to differences in the proportions of leukocytes. The association of the methylation changes with gene expression levels was also investigated in the same individuals. Results: By applying Illumina 450K array technology and a two-step analysis process, we identified 8540 high-confidence ageing-associated CpG sites, 46% of which were hypermethylated in nonagenarians. The hypermethylation-associated genes belonged to a common category, and they were predicted to be regulated by a common group of transcription factors and were enriched in a related set of GO terms and canonical pathways. On the contrary, the hypomethylation-associated genes appeared to be a more random group, as only a limited set of GO terms and canonical pathways were identified in this group. Among the 8540 CpG sites associated with ageing, there was an association with gene expression levels in 377. The genes displaying methylation-regulated expression were enriched in GO terms and canonical pathways associated with immune system functions, particularly phagocytosis. Conclusions: According to our results, certain ageing-associated immune-system impairments may be mediated via changes in DNA methylation. The results also imply that ageing-associated hypo- and hypermethylation are distinct processes: hypermethylation could be caused by programmed changes, while hypomethylation could be the result of environmental and stochastic processes.
2015-03-20 | GSE58888 | GEO
Project description:Increased protein misfolding and aggregation are key hallmarks of ageing and many age-related diseases. As generating and maintaining a functional proteome (proteostasis) is crucial to every cellular process, this age-related decline in proteostasis is suggested to play a primary role in the breakdown of diverse cellular subsystems during ageing. Indeed, augmented proteostasis pathways are associated with extended lifespan across different species. With the ribosome as the earliest proteostasis checkpoint, decreased protein synthesis is also a conserved mechanism that extends lifespan. Yet, it remains unclear whether ageing impacts translation after initiation. Here, we use worms and yeast to investigate how ageing influences translation elongation. We show an age-dependent increase in ribosome pausing at diverse positions in coding sequences. This pausing is conserved in both worms and yeast, particularly at Arg and polybasic regions. We further show that such pausing is associated with the age-dependent aggregation of truncated nascent proteins involved in proteostasis pathways, notably aminoacyl tRNA synthetases. Moreover, we find that impairment in clearing truncated nascent proteins is associated with decreased lifespan. These data establish elongation kinetics and co-translational quality control as critical contributors of the age-related proteostasis collapse, which may precipitate the systemic decline observed during ageing.
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Project description:This SuperSeries is composed of the following subset Series: GSE30721: Profiling proteome-scale antibody responses to M. tuberculosis proteins in sera of macaques infected with M. tuberculosis GSE30722: Profiling proteome-scale antibody responses to M. tuberculosis proteins in TB suspect's sera Refer to individual Series
2012-07-05 | E-GEOD-31368 | biostudies-arrayexpress
Project description:Human infection with Mycobacterium tuberculosis results in a continuum of ill-defined, clinical manifestations with stable latent M. tuberculosis infection (LTBI) and severe active disease at the ends. Identifying different states of infection is of importance to tuberculosis (TB) control since risk of developing active disease varies among different asymptomatic states while infectiousness varies among patients with different bacterial burden. We investigated changes in proteome-scale antibody responses during disease progression in a non-human primate model of tuberculosis. We probed M. tuberculosis proteome microarrays with serial sera collected from three infection-outcome groups (active, reactivation, and latent). We found that each infection outcome is associated with characteristic changes in the antibody levels and number of antigenic targets, which suggested an association between antibody responses and bacillary burden. Additional proteome-scale serological profiling of > 400 human TB suspects established that antibody responses are positively associated with bacterial load. Thus tuberculosis-specific antibody levels and number of antigenic targets increases with disease progression.
2012-07-06 | GSE30722 | GEO
Project description:Understanding the immune response to tuberculosis requires greater knowledge of humoral responses. To characterize antibody targets and the effect of disease parameters on target recognition, we developed a systems immunology approach that integrated detection of antibodies against the entire Mycobacterium tuberculosis proteome, bacterial metabolic and regulatory pathway information, and patient data. Probing ~4,000 M. tuberculosis proteins with sera from >500 suspected tuberculosis patients worldwide revealed that antibody responses recognized ~10% of the bacterial proteome. This result defines the immunoproteome of M. tuberculosis, which is rich in membrane-associated and extracellular proteins. Most serum reactivity during active tuberculosis focused onto ~0.5% of the proteome. Within this pool, which is selectively enriched for extracellular proteins (but not for membrane-associated proteins), relative target preference varied among patients. The shift in relative M. tuberculosis protein reactivity observed with active tuberculosis defines the evolution of the humoral immune response during M. tuberculosis infection and disease. Peripheral blood was collected from prospectively enrolled TB suspects among subjects seeking care for pulmonary symptoms at clinics associated with national TB control programs in 11 countries. M. tuberculosis proteome microarrays representing 4099 bacterial protein spots were probed with sera from 561 TB suspects. Based on the final diagnosis, they belonged to two classes: TB (n=254) and Non-TB Disease (n=307). In addition, healthy individuals negative to Latent TB Infection (LTBI neg, n=64) were also tested (negative control sera). Each serum was tested with a single array and no replicate experiments were performed. The reactivity of a serum to an M. tuberculosis protein (reactivity call) was defined based on the distribution of negative control sera intensity for that protein using Z-statistics. Based on the distribution of reactivity calls, 27 outlier samples reacting with more than 20 proteins were excluded from further analysis. The association of reactivity calls of each protein with TB/NTBD status of TB suspects was determined by estimating odds ratio and 95% confidence interval.
2010-07-13 | E-GEOD-19433 | biostudies-arrayexpress
Project description:Human infection with Mycobacterium tuberculosis results in a continuum of ill-defined, clinical manifestations with stable latent M. tuberculosis infection (LTBI) and severe active disease at the ends. Identifying different states of infection is of importance to tuberculosis (TB) control since risk of developing active disease varies among different asymptomatic states while infectiousness varies among patients with different bacterial burden. We investigated changes in proteome-scale antibody responses during disease progression in a non-human primate model of tuberculosis. We probed M. tuberculosis proteome microarrays with serial sera collected from three infection-outcome groups (active, reactivation, and latent). We found that each infection outcome is associated with characteristic changes in the antibody levels and number of antigenic targets, which suggested an association between antibody responses and bacillary burden. Additional proteome-scale serological profiling of > 400 human TB suspects established that antibody responses are positively associated with bacterial load. Thus tuberculosis-specific antibody levels and number of antigenic targets increases with disease progression. Serum samples collected from adult patients with suspected tuberculosis during a multi-site study was used to probe whole proteome microarrays. Subject recruitment was conducted under uniform protocols approved by the institutional ethics committee at each site. Final diagnosis of active TB was based on positive M. tuberculosis culture results. The active TB patients were further subdivided into smear-positive and negative disease based on results of Ziehl-Neelsen staining of sputum smears for acid fast bacilli. Active TB was excluded as a diagnosis (Non-TB Disease [NTBD] patients) based on having negative M. tuberculosis culture and smear results and on having an alternate diagnosis. All subjects were presumably negative for HIV infection given the very low incidence of HIV infection in the study sites. Sera from 169 TB and 242 NTBD patients were selected for microarray probing. The control sera (n = 14) which was used to generate negative control distribution for each protein were negative to latent M. tuberculosis infection, as indicated by negative results to tuberculin skin test.
2012-07-05 | E-GEOD-30722 | biostudies-arrayexpress
Project description:Human infection with Mycobacterium tuberculosis results in a continuum of ill-defined, clinical manifestations with stable latent M. tuberculosis infection (LTBI) and severe active disease at the ends. Identifying different states of infection is of importance to tuberculosis (TB) control since risk of developing active disease varies among different asymptomatic states while infectiousness varies among patients with different bacterial burden. We investigated changes in proteome-scale antibody responses during disease progression in a non-human primate model of tuberculosis. We probed M. tuberculosis proteome microarrays with serial sera collected from three infection-outcome groups (active, reactivation, and latent). We found that each infection outcome is associated with characteristic changes in the antibody levels and number of antigenic targets, which suggested an association between antibody responses and bacillary burden. Additional proteome-scale serological profiling of > 400 human TB suspects established that antibody responses are positively associated with bacterial load. Thus tuberculosis-specific antibody levels and number of antigenic targets increases with disease progression. To investigate antibody responses during the course of infection, we probed M. tuberculosis proteome microarrays with serial sera collected from experimentally infected cynomolgus macaques. Based on infection outcome, the macaques were grouped into three classes; A) active disease (n = 4), B) latent infection (n=5) and C) reactivation disease (n = 5). Note that the macaques in the reactivation class developed signs of disease spontaneously without any experimental intervention. For each animal, we tested one pre-infection time point and approximately ten post-infection time points at one-month intervals.
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Project description:Understanding the immune response to tuberculosis requires greater knowledge of humoral responses. To characterize antibody targets and the effect of disease parameters on target recognition, we developed a systems immunology approach that integrated detection of antibodies against the entire Mycobacterium tuberculosis proteome, bacterial metabolic and regulatory pathway information, and patient data. Probing ~4,000 M. tuberculosis proteins with sera from >500 suspected tuberculosis patients worldwide revealed that antibody responses recognized ~10% of the bacterial proteome. This result defines the immunoproteome of M. tuberculosis, which is rich in membrane-associated and extracellular proteins. Most serum reactivity during active tuberculosis focused onto ~0.5% of the proteome. Within this pool, which is selectively enriched for extracellular proteins (but not for membrane-associated proteins), relative target preference varied among patients. The shift in relative M. tuberculosis protein reactivity observed with active tuberculosis defines the evolution of the humoral immune response during M. tuberculosis infection and disease.
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