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Landscape of stimulation-responsive chromatin across diverse human immune cells.

ABSTRACT: A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Allele-specific read mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need to characterize the effects of genetic variation in stimulated cells.

SUBMITTER: Calderon D

PROVIDER: S-EPMC6858557 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Landscape of stimulation-responsive chromatin across diverse human immune cells.

Calderon Diego D Nguyen Michelle L T MLT Mezger Anja A Kathiria Arwa A Müller Fabian F Nguyen Vinh V Lescano Ninnia N Wu Beijing B Trombetta John J Ribado Jessica V JV Knowles David A DA Gao Ziyue Z Blaeschke Franziska F Parent Audrey V AV Burt Trevor D TD Anderson Mark S MS Criswell Lindsey A LA Greenleaf William J WJ Marson Alexander A Pritchard Jonathan K JK

Nature genetics 20190930 10

A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response eleme ...[more]

PMID: 31570894

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Project description:BackgroundImmunotherapy is a rapidly evolving treatment option in breast cancer; However, the breast cancer immune microenvironment is understudied in Black and younger (<50 years) patients.MethodsWe used histologic and RNA-based immunoprofiling methods to characterize the breast cancer immune landscape in 1,952 tumors from the Carolina Breast Cancer Study (CBCS), a population-based study that oversampled Black (n = 1,030) and young women (n = 1,039). We evaluated immune response leveraging markers for 10 immune cell populations, compared profiles to those in The Cancer Genome Atlas (TCGA) Project [n = 1,095 tumors, Black (n = 183), and young women (n = 295)], and evaluated in association with clinical and demographic variables, including recurrence.ResultsConsensus clustering identified three immune clusters in CBCS (adaptive-enriched, innate-enriched, or immune-quiet) that varied in frequency by race, age, tumor grade and subtype; however, only two clusters were identified in TCGA, which were predominantly comprised of adaptive-enriched and innate-enriched tumors. In CBCS, the strongest adaptive immune response was observed for basal-like, HER2-positive (HER2+), triple-negative breast cancer (TNBC), and high-grade tumors. Younger patients had higher proportions of adaptive-enriched tumors, particularly among estrogen receptor (ER)-negative (ER-) cases. Black patients had higher frequencies of both adaptive-enriched and innate-enriched tumors. Immune clusters were associated with recurrence among ER- tumors, with adaptive-enriched showing the best and innate-enriched showing the poorest 5-year recurrence-free survival.ConclusionsThese data suggest that immune microenvironments are intricately related to race, age, tumor subtype, and grade.ImpactGiven higher mortality among Black and young women, more defined immune classification using cell-type-specific panels could help explain higher recurrence and ultimately lead to targetable interventions.

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Landscape of stimulation-responsive chromatin across diverse human immune cells.

Publications

Landscape of stimulation-responsive chromatin across diverse human immune cells.

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