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Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential.

ABSTRACT: Human memory T cells (MTC) are poised to rapidly respond to antigen re-exposure. Here, we derived the transcriptional and epigenetic programs of resting and ex vivo activated, circulating CD4⁺ and CD8⁺ MTC subsets. A progressive gradient of gene expression from naïve to T_CM to T_EM is observed, which is accompanied by corresponding changes in chromatin accessibility. Transcriptional changes suggest adaptations of metabolism that are reflected in altered metabolic capacity. Other differences involve regulatory modalities comprised of discrete accessible chromatin patterns, transcription factor binding motif enrichment, and evidence of epigenetic priming. Basic-helix-loop-helix factor motifs for AHR and HIF1A distinguish subsets and predict transcription networks to sense environmental changes. Following stimulation, primed accessible chromatin correlate with an augmentation of MTC gene expression as well as effector transcription factor gene expression. These results identify coordinated epigenetic remodeling, metabolic, and transcriptional changes that enable MTC subsets to ultimately respond to antigen re-encounters more efficiently.

SUBMITTER: Rose JR

PROVIDER: S-EPMC10070634 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential.

Rose James R JR Akdogan-Ozdilek Bagdeser B Rahmberg Andrew R AR Powell Michael D MD Hicks Sakeenah L SL Scharer Christopher D CD Boss Jeremy M JM

Communications biology 20230403 1

Human memory T cells (MTC) are poised to rapidly respond to antigen re-exposure. Here, we derived the transcriptional and epigenetic programs of resting and ex vivo activated, circulating CD4+ and CD8+ MTC subsets. A progressive gradient of gene expression from naïve to TCM to TEM is observed, which is accompanied by corresponding changes in chromatin accessibility. Transcriptional changes suggest adaptations of metabolism that are reflected in altered ...[more]

PMID: 37012418

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Project description:RationaleThere is growing evidence that common variants and rare sequence alterations in regulatory sequences can result in birth defects or predisposition to disease. Congenital heart defects are the most common birth defect and have a clear genetic component, yet only a third of cases can be attributed to structural variation in the genome or a mutation in a gene. The remaining unknown cases could be caused by alterations in regulatory sequences.ObjectiveIdentify regulatory sequences and gene expression networks that are active during organogenesis of the human heart. Determine whether these sites and networks are enriched for disease-relevant genes and associated genetic variation.Methods and resultsWe characterized ChromHMM (chromatin state) and gene expression dynamics during human heart organogenesis. We profiled 7 histone modifications in embryonic hearts from each of 9 distinct Carnegie stages (13-14, 16-21, and 23), annotated chromatin states, and compared these maps to over 100 human tissues and cell types. We also generated RNA-sequencing data, performed differential expression, and constructed weighted gene coexpression networks. We identified 177 412 heart enhancers; 12 395 had not been previously annotated as strong enhancers. We identified 92% of all functionally validated heart-positive enhancers (n=281; 7.5× enrichment; P<2.2×10-16). Integration of these data demonstrated novel heart enhancers are enriched near genes expressed more strongly in cardiac tissue and are enriched for variants associated with ECG measures and atrial fibrillation. Our gene expression network analysis identified gene modules strongly enriched for heart-related functions, regulatory control by heart-specific enhancers, and putative disease genes.ConclusionsWell-connected hub genes with heart-specific expression targeted by embryonic heart-specific enhancers are likely disease candidates. Our functional annotations will allow for better interpretation of whole genome sequencing data in the large number of patients affected by congenital heart defects.

Dataset Information

Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential.

Publications

Distinct transcriptomic and epigenomic modalities underpin human memory T cell subsets and their activation potential.

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