Metadomain genome associations in mammalian T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE276057 | GEO | 2026/06/25
REPOSITORIES: GEO
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Project description:There is a paucity of information regarding 3-dimensional (3D) chromatin interactions and chromosomal organization in different mammalian cell types. For example, the relationships between different topologically associating domains (TADs) and sub-TAD regulatory loops are uncertain due to the lack of appropriate computational tools and high-resolution experimental data. Herein, we developed a computational methodology for studying chromosomal organization across scales and applied it to high-resolution chromosome conformation capture (Hi-C) data using activatory and inhibitory lineages of T lymphocytes as a model. We identified shared and cell type-specific TADs and sub-TAD loops at 5 Kb resolution. Global analysis revealed megabase-scale and inter-chromosomal interactions, including many cell type-specific meta-TAD associations (meta-domains) containing multiple functionally important genes such as Ctla4, Ikzf2, Ets1, Lef1, Runx1, Bach2, Foxo1 and others. Reanalysis of published data confirmed the reproducibility of these metadomain interactions in both mouse and human T cells. Genome-wide metadomain clustering identified several intra-chromosomal and three inter-chromosomal hubs with distinct histone marks, indicating compartment-like structures, with one active hub linked to general gene activation across immune cells and another being highly specific to T cells. Building and analyzing a compendium of new and public epigenomic T cell data enabled identification of ultra-long-range meta-loop interactions underlying metadomains and inference of distinct architectural factors associated with short-range sub-TAD loops and long-range metaloops. Altogether, our study reveals new cell type-specific 3D chromosomal structures across scales in T cells. The computational methodology is broadly applicable to analyses of 3D genome organization across different cell types and experimental systems.
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Project description:Multiple common variants for celiac disease influencing immune gene expression The goal of this study was to study the effect of genetic variation on gene expression of untouched primary leucocytes. We obtained peripheral blood RNA from unrelated Dutch and UK individuals using PAXgene tubes. We performed a second-generation genome wide association study of 4,533 celiac disease cases and 10,750 controls. We genotyped 113 selected SNPs with PGWAS<10-4, and 18 SNPs from 14 known loci, in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome wide significance (Pcombined<5x10-8), most contain immune function genes (BACH2, CCR4, CD80, CIITA/SOCS1/CLEC16A, ICOSLG, ZMIZ1) with ETS1, RUNX3, THEMIS and TNFRSF14 playing key roles in thymic T cell selection. A further 13 regions had suggestive association evidence. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P<0.0028, FDR 5%) with cis gene expression. *** Due to privacy concerns, the SNP data is not available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access directly from the submitter (contact info below). ***
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Project description:Multiple common variants for celiac disease influencing immune gene expression The goal of this study was to study the effect of genetic variation on gene expression of untouched primary leucocytes. We obtained peripheral blood RNA from unrelated Dutch individuals using PAXgene tubes. We performed a second-generation genome wide association study of 4,533 celiac disease cases and 10,750 controls. We genotyped 113 selected SNPs with PGWAS<10-4, and 18 SNPs from 14 known loci, in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome wide significance (Pcombined<5x10-8), most contain immune function genes (BACH2, CCR4, CD80, CIITA/SOCS1/CLEC16A, ICOSLG, ZMIZ1) with ETS1, RUNX3, THEMIS and TNFRSF14 playing key roles in thymic T cell selection. A further 13 regions had suggestive association evidence. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P<0.0028, FDR 5%) with cis gene expression. *** Due to privacy concerns, the SNP data is not available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access directly from the submitter (contact info below). ***
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