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Transcript-indexed ATAC-seq reveals paired single-cell T cell receptor identity and chromatin accessibility for precision immune profiling [single cell]

ABSTRACT: T cells create vast amounts of diversity in their T cell receptor (TCR) genes, enabling individual clones to recognize particular peptide-MHC ligands. Here we combine transposase accessible chromatin analysis and TCR sequencing (T-ATAC-seq) at the single-cell level. Using this approach, we identify epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers, and primary leukemic T cells from clinical patient samples. In healthy peripheral blood CD4+ T cells, we identify cis and trans regulators of naive and memory T cell states and find significant heterogeneity in surface marker-defined populations. In patients with cutaneous T cell lymphoma, we identify leukemic and non-leukemic regulatory pathways in cells from the same individual, which has been previously challenging. Thus, T-ATAC-seq is a new tool enabling analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity, and immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107816 | GEO | 2018/01/15

SECONDARY ACCESSION(S): PRJNA421486

REPOSITORIES: GEO

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Transcript-indexed ATAC-seq reveals paired single-cell T cell receptor identity and chromatin accessibility for precision immune profiling [Ensembl]

Project description:T cells create vast amounts of diversity in their T cell receptor (TCR) genes, enabling individual clones to recognize particular peptide-MHC ligands. Here we combine transposase accessible chromatin analysis and TCR sequencing (T-ATAC-seq) at the single-cell level. Using this approach, we identify epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers, and primary leukemic T cells from clinical patient samples. In healthy peripheral blood CD4+ T cells, we identify cis and trans regulators of naive and memory T cell states and find significant heterogeneity in surface marker-defined populations. In patients with cutaneous T cell lymphoma, we identify leukemic and non-leukemic regulatory pathways in cells from the same individual, which has been previously challenging. Thus, T-ATAC-seq is a new tool enabling analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity, and immunotherapy.

2018-01-15 | GSE107223 | GEO

Nanowell-based single-cell combinatorial indexed ATAC-seq

Project description:Here we present advancements in single-cell combinatorial indexed ATAC-seq (sciATAC) to measure chromatin accessibility that leverage nanowell chips to achieve atlas-scale cell throughput (>105) at low cost. Our optimized techniques also achieve a high fraction of reads that fall within called peaks (>80%) and low cell doublet rates. We also demonstrate an alternative workflow that achieves high cell coverage while retaining exceptional enrichment for open chromatin regions, enabling the assessment of >70,000 unique accessible loci per cell.

2023-02-08 | GSE218881 | GEO

Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position

Project description:We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500–50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with the nucleosome. Using ATAC-seq maps of human CD4+ T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual’s epigenome on a timescale compatible with clinical decision-making. We examined chromatin structure using ATAC-seq in 2 cell types (GM12878 cell line, purified CD4+ T cells).

2013-10-01 | E-GEOD-47753 | biostudies-arrayexpress

WAT3R: Recovery of T-Cell Receptor Variable Regions From 3’ Single-Cell RNA-Sequencing

Project description:Diversity of the T-cell receptor (TCR) repertoire is central to adaptive immunity. The TCR is composed of α and β chains, encoded by the TRA and TRB genes, of which the variable regions determine antigen specificity. To generate novel biological insights into the complex functioning of immune cells, combined capture of variable regions and single-cell transcriptomes provides a compelling approach. Recent developments enable the enrichment of TRA and TRB variable regions from widely used technologies for 3’-biased single-cell RNA-sequencing (scRNA-seq). However, a comprehensive computational pipeline to process TCR-enriched data from 3’ scRNA-seq is not available. Here we present an analysis pipeline to process TCR variable regions enriched from 3’ scRNA-seq cDNA. The tool reports TRA and TRB nucleotide and amino acid sequences linked to cell barcodes, enabling the reconstruction of T-cell clonotypes with associated transcriptomes. We demonstrate the software using peripheral blood mononuclear cells (PBMCs) from a healthy donor and detect TCR sequences in a high proportion of single T-cells. Detection of TCR sequences is negligible in non-T-cell populations, demonstrating specificity. Finally, we show that TCR clones are larger in CD8 Memory T-cells than other T-cell types, indicating an association between T-cell clonotypes and differentiation states.

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T Cell Responses to Varicella Zoster Virus

Project description:<p>Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood is able to escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-specific CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. While all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly among different individuals. A genetic influence was seen for the sharing of individual TCR sequences from antigen-specific cells, but not for repertoire richness or the selection of clonal dominance. VZV vaccination favored the expansion of infrequent VZV-specific TCRs including those from naïve T cells while leaving dominant T cell clones mostly unaffected.</p>

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Project description:The impact of healthy aging on molecular programming of immune cells is poorly understood. Here, we report comprehensive characterization of healthy aging in human classical monocytes, with a focus on epigenomic, transcriptomic, and proteomic alterations, as well as the corresponding proteomic and metabolomic data for plasma, using healthy cohorts of 20 young and 20 older males (~27 and ~64 years old on average). For each individual, we performed eRRBS-based DNA methylation profiling, which allowed us to identify a set of age-associated differentially methylated regions (DMRs) – a novel, cell-type specific signature of aging in DNA methylome. Hypermethylation events were associated with H3K27me3 in the CpG islands near promoters of lowly-expressed genes, while hypomethylated DMRs were enriched in H3K4me1 marked regions and associated with age-related increase of expression of the corresponding genes, providing a link between DNA methylation and age-associated transcriptional changes in primary human cells.

2022-02-16 | PXD021821 | Pride

Mus musculus

Project description:ATAC-seq analysis of leukemic stem cells

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Mus musculus

Project description:ATAC-seq analysis of Lineage+ leukemic cells

| PRJDB8831 | ENA

Chromatin accessibility landscape of cutaneous T cell lymphoma and dynamic response to HDAC inhibitors

Project description:Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by Assay of Transposase-Accessible Chromatin (ATAC-seq). Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic vs. non-leukemic (host) CD4+ T cells in CTCL patients, vs. CD4+ T cells in healthy donors. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4+ T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.

2017-04-20 | GSE85853 | GEO

Progression from the preleukemic stage to acute leukemia in TAL1/SCL-LMO1 transgenic mice

Project description:The TAL1/SCL and LMO1 oncogenic transcription factors establish a pre-leukemic state by reprogramming thymocytes into self-renewing pre-leukemic stem cells (pre-LSCs). Pre-TCR signaling accelerates the progression to T-cell acute lymphoblastic leukemia (T-ALL). To directly address the importance of pre-TCR signaling in driving progression to T-ALL, we leverage on Cd3-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated. In the absence of pre-TCR signaling in Cd3ε-deficient SCL-LMO1 transgenic mice, T-ALL onset is delayed by 150 days. Despite the absence of pre-TCR/CD3 signaling in these mice, we show that leukemic thymocytes exhibit the gene expression profiles of thymocytes that have undergone β-selection, i.e. exhibiting a re-activation of pre-TCR-driven proliferation signature, and a down regulation of HEB/TCF12 target genes. Lastly, monoallelic deletion of Heb is sufficient to accelerate T-ALL onset in Cd3ε-deficient SCL-LMO1 transgenic mice. Together, these results underscore the role of HEB/TCF12 as a tumor suppressor in T-ALL.

2022-03-27 | GSE198506 | GEO

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