2014
DOI: 10.1038/ni.2937
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Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility

Abstract: A characteristic feature of asthma is the aberrant accumulation, differentiation or function of memory CD4+ T cells that produce type 2 cytokines (TH2 cells). By mapping genome-wide histone modification profiles for subsets of T cells isolated from peripheral blood of healthy and asthmatic individuals, we identified enhancers with known and potential roles in the normal differentiation of human TH1 cells and TH2 cells. We discovered disease-specific enhancers in T cells that differ between healthy and asthmati… Show more

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Cited by 157 publications
(184 citation statements)
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“…Analysis of histone modifications associated with regulatory activity (e.g., H3K4me1/2) and DNase I hypersensitive sites assayed by the ENCODE Project 17 in an LCL (GM12878) identified four PREs in this region, named PRE1 to PRE4 ( Figure 1C). Consistent with these results, Seumois et al 18 detected a significant gain in H3K4me2, which marks both active and poised enhancers, in PRE1 and PRE2 when comparing primary human CD4 þ memory T cells against naive CD4 þ T cells. Similarly, Hnisz et al 19 predicted PRE3 to be an enhancer in multiple human immune cell types.…”
supporting
confidence: 54%
See 1 more Smart Citation
“…Analysis of histone modifications associated with regulatory activity (e.g., H3K4me1/2) and DNase I hypersensitive sites assayed by the ENCODE Project 17 in an LCL (GM12878) identified four PREs in this region, named PRE1 to PRE4 ( Figure 1C). Consistent with these results, Seumois et al 18 detected a significant gain in H3K4me2, which marks both active and poised enhancers, in PRE1 and PRE2 when comparing primary human CD4 þ memory T cells against naive CD4 þ T cells. Similarly, Hnisz et al 19 predicted PRE3 to be an enhancer in multiple human immune cell types.…”
supporting
confidence: 54%
“…The size of the interaction products amplified was confirmed by gel electrophoresis and their sequence verified by Sanger sequencing; similar results were also obtained in two additional independent replicates of each sample ( Figure S3). Fragment F9 is 1.1 kb long and overlaps the centromeric end of PRE2, including the peak region of H3K4me2 gain observed by Seumois et al 18 in memory CD4 þ T cells. Interactions with fragment F9 were observed in LCLs homozygote for the rs7009110:C protective allele but not (or less frequently) for the T predisposing allele.…”
mentioning
confidence: 74%
“…Quantitative trait studies in human cells suggest that genetic variation has detectable effects of transcription factor binding, gene expression, and chromatin state of regulatory elements (110). Although not statistically significant, recent work suggests that genetic variants associated with asthma risk can be found at Th2 cell enhancers that are differentially active between asthma patients and healthy controls (111). Such studies are beginning to characterize the functional effects of causal autoimmune disease variants in modulating transcription factor binding, chromatin state, gene regulation, and cellular phenotype.…”
Section: Novel Approaches To Determining the Significance Of Genetic mentioning
confidence: 99%
“…This implicates gene regulatory processes in disease etiology and provides an important resource for understanding the molecular basis of human diseases including SLE, such as mechanistic insights into the likely relevant cell types underlying genome-wide significant loci. For example, Seumois et al [2014] discovered that asthma-specific enhancers in T cells that differed between healthy individuals and those with asthma and also gained H3K4me2 mark during T H 2 cell development showed the highest enrichment for asthma-associated SNPs. This strategy can be applied to any accessible cell type that is relevant to human disease and allows for enhancer profiling.…”
Section: ) Collect All Genetic and Epigenetic Aberrations For Diagnomentioning
confidence: 99%
“…This strategy can be applied to any accessible cell type that is relevant to human disease and allows for enhancer profiling. Combining this biggest reference of human epige nomes with several other companion papers that further explored the datasets in the context of autoimmune diseases [Seumois et al, 2014;Farh et al, 2015], a most extensive and SLE-specific reference human epigenome can be generated. With the cost of next-generation sequencing further decreased, various diagnostic methods based on this method become powerful and standard procedures to collect individual disease-causing genes or regulatory gene variants including epigenetic variations [Jones et al, 2014].…”
Section: ) Collect All Genetic and Epigenetic Aberrations For Diagnomentioning
confidence: 99%