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Multimodal profiling of 500,000 memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment, and disease

ABSTRACT: Multimodal profiling of 500,000 memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment, and disease

PROVIDER: PRJNA738562 | ENA |

REPOSITORIES: ENA

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Multimodal profiling of 500,000 memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment, and disease

Project description:Multimodal profiling of 500,000 memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment, and disease

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Multimodal profiling of 500,000 memory T cells from a tuberculosis cohort

Project description:Multimodal profiling of 500,000 memory T cells from a tuberculosis cohort

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Multimodally profiling memory T cells from a tuberculosis cohort identifies cell state associations with demographics, environment and disease.

Project description:Multimodal T cell profiling can enable more precise characterization of elusive cell states underlying disease. Here, we integrated single-cell RNA and surface protein data from 500,089 memory T cells to define 31 cell states from 259 individuals in a Peruvian tuberculosis (TB) progression cohort. At immune steady state >4 years after infection and disease resolution, we found that, after accounting for significant effects of age, sex, season and genetic ancestry on T cell composition, a polyfunctional type 17 helper T (TH17) cell-like effector state was reduced in abundance and function in individuals who previously progressed from Mycobacterium tuberculosis (M.tb) infection to active TB disease. These cells are capable of responding to M.tb peptides. Deconvoluting this state-uniquely identifiable with multimodal analysis-from public data demonstrated that its depletion may precede and persist beyond active disease. Our study demonstrates the power of integrative multimodal single-cell profiling to define cell states relevant to disease and other traits.

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Exome Sequencing to Identify Medically Relevant Associations in Finnish Sub-Isolate Samples from the FINRISK Cohort

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Associations with early life socio-economic position in adult DNA methylation

Project description:Comparison of whole blood DNA methylation in 45 year-old humans with low and high childhood and adulthood socio-economic position Background: Disadvantaged socio-economic position (SEP) in childhood is associated with increased adult mortality and morbidity. We aimed to establish whether childhood SEP was associated with differential methylation of adult DNA. Methods: Forty adult males from the 1958 British Birth Cohort Study were selected from SEP extremes in both early childhood and mid-adulthood. We performed genome-wide methylation analysis on blood DNA taken at 45y using MeDIP (methylated DNA immunoprecipitation). We mapped in triplicate the methylation state of promoters of ~20,000 genes and 400 microRNAs. Probe methylation scores were averaged across triplicates and differential methylation between groups of individuals was determined. Differentially methylated promoter sites of selected genes were validated using pyrosequencing of bisulfite-converted DNA. Results: 9,112 variably methylated probes (from N=223,359 on the microarray) corresponded to 6,176 gene promoters with at least one variable probe. Unsupervised hierarchical clustering of probes obtained from the 500 most variable promoters revealed a cluster enriched with high SEP individuals confirming that SEP differences contribute to overall epigenetic variation. Methylation levels for 1252 gene promoters were associated with childhood SEP vs 545 promoters for adulthood SEP. Functionally, associations with childhood SEP appear in promoters of genes enriched in key cell signalling pathways. The differentially methylated promoters associated with SEP cluster in megabase-sized regions of the genome. Conclusions: Adult blood DNA methylation profiles show more associations with childhood SEP than adult SEP. Organization of these associations across the genome suggests a well-defined epigenetic pattern linked to early socio-economic environment.

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