scholarly journals Molecular diversification of regulatory T cells in nonlymphoid tissues

2018 ◽  
Vol 3 (27) ◽  
pp. eaat5861 ◽  
Author(s):  
Joanna R. DiSpirito ◽  
David Zemmour ◽  
Deepshika Ramanan ◽  
Jun Cho ◽  
Rapolas Zilionis ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Chromatin Accessibility ◽  
Lymphoid Organs ◽  
Specific Gene ◽  
Open Chromatin ◽  
Binding Motifs ◽  
Nonlymphoid Tissue ◽  
Visceral Adipose ◽  
Accessible Chromatin

Foxp3+CD4+regulatory T cells (Tregs) accumulate in certain nonlymphoid tissues, where they control diverse aspects of organ homeostasis. Populations of tissue Tregs, as they have been termed, have transcriptomes distinct from those of their counterparts in lymphoid organs and other nonlymphoid tissues. We examined the diversification of Tregsin visceral adipose tissue, skeletal muscle, and the colon vis-à-vis lymphoid organs from the same individuals. The unique transcriptomes of the various tissue Tregpopulations resulted from layering of tissue-restricted open chromatin regions over regions already open in the spleen, the latter tagged by super-enhancers and particular histone marks. The binding motifs for a small number of transcription factor (TF) families were repeatedly enriched within the accessible chromatin stretches of Tregsin the three nonlymphoid tissues. However, a bioinformatically and experimentally validated transcriptional network, constructed by integrating chromatin accessibility and single-cell transcriptomic data, predicted reliance on different TF families in the different tissues. The network analysis also revealed that tissue-restricted and broadly acting TFs were integrated into feed-forward loops to enforce tissue-specific gene expression in nonlymphoid-tissue Tregs. Overall, this study provides a framework for understanding the epigenetic dynamics of T cells operating in nonlymphoid tissues, which should inform strategies for specifically targeting them.

scholarly journals Epigenetic and Transcriptional Dysregulation in CD4+ T cells of Patients with Atopic Dermatitis

2021 ◽  
Author(s):  
Amy A. Eapen ◽  
Sreeja Parameswaran ◽  
Carmy Forney ◽  
Lee E. Edsall ◽  
Daniel Miller ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Atopic Dermatitis ◽  
Genetic Risk ◽  
Cd4 T Cells ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Binding Motifs ◽  
Risk Variants ◽  
Dna Binding Motifs

ABSTRACTAtopic dermatitis (AD) is one of the most common skin disorders in children. Disease etiology involves genetic and environmental factors, with the 29 independent AD risk loci enriched for risk allele-dependent gene expression in the skin and CD4+ T cell compartments. We investigated epigenetic mechanisms that may account for genetic susceptibility in CD4+ T cells. To understand gene regulatory activity differences in peripheral blood T cells in AD, we measured chromatin accessibility (ATAC-seq), NFKB1 binding (ChIP-seq), and gene expression (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD and age-matched, non-allergic controls. Open chromatin regions in stimulated CD4+ T cells were highly enriched for AD genetic risk variants, with almost half of AD risk loci overlapping with AD-dependent ATAC-seq peaks. AD-specific open chromatin regions were strongly enriched for NFκB DNA binding motifs. ChIP-seq identified hundreds of NFKB1-occupied genomic loci that were AD-specific or Control-specific. As expected, the AD-specific ChIP-seq peaks were strongly enriched for NFκB DNA binding motifs. Surprisingly, Control-specific NKFB1 ChIP-seq peaks were not enriched for NFKB1 motifs, instead containing motifs for other classes of human TFs, suggesting a mechanism involving altered indirect NFKB1 binding. Using DNA sequencing data, we identified 63 instances of genotype-dependent chromatin accessibility at 36 AD risk variants (30% of AD risk loci) that could lead to genotype-dependent expression at these loci. We propose that CD4+ T cells respond to stimulation in an AD-specific manner, resulting in disease and genotype-dependent chromatin accessibility involving NFKB binding.AUTHOR SUMMARYStimulated CD4+ T cells from patients with atopic dermatitis have disease-dependent regulation of how gene expression is regulated. This regulation is disease dependent and the way the DNA is accessible and the transcription factor NFKB1 binds is enriched for genetic risk variants. Clinically, the CD4+ T cells in the peripheral blood of patients with AD respond to stimulation in a disease and genotype-dependent manner.

scholarly journals Wnt/β-catenin activation epigenetically reprograms Regulatory T cells in IBD and progression to dysplasia.

2020 ◽  
Author(s):  
Fotini Gounari ◽  
Jasmin Quandt ◽  
Stephen Arnovitz ◽  
Leila Haghi ◽  
Janine Woehlk ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
T Cells ◽  
Regulatory T Cells ◽  
Functional Diversity ◽  
Bowel Disease ◽  
Elevated Expression ◽  
Inflammatory Bowel ◽  
Ifn Γ ◽  
Accessible Chromatin

Abstract The molecular and functional diversity of regulatory T-cells (Tregs) in health and in disease remains unclear. We previously described in colorectal cancer (CRC) patients a subpopulation of RORγt+ Tregs with elevated expression of β-catenin and pro-inflammatory properties. Here we observed progressive expansion of RORγt+ Tregs in inflammatory bowel disease (IBD) patients during inflammation and early dysplasia. Activating Wnt/β-catenin signaling in human and murine Tregs was sufficient to recapitulate the disease-associated increase in frequencies of RORγt+ Tregs expressing IL-17, IFN-γ, and TNFa. We found that binding of the β-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt/β-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Tregs. Activation of ꞵ-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.

scholarly journals Terminal selectors organize postmitotic chromatin accessibility for acquisition of serotonergic identity

2021 ◽  
Author(s):  
Xinrui L Zhang ◽  
William C Spencer ◽  
Nobuko Tabuchi ◽  
Evan S Deneris
Keyword(s):  
Single Cell ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Regulatory Sequences ◽  
Early Maturation ◽  
Accessible Chromatin

Assembly of transcriptomes encoding unique neuronal identities requires selective accessibility of regulatory inputs to cis-regulatory sequences in nucleosome-embedded chromatin. Yet the mechanisms involved in shaping postmitotic neuronal chromatin are poorly understood. Here we used ATAC-seq, ChIPmentation, and single-cell analyses to show that unique distal enhancers and super-enhancers define the Pet1 neuron lineage that generates serotonin (5-HT) neurons. Heterogeneous single cell chromatin landscapes are established early in postmitotic Pet1 neurons and reveal the regulatory programs driving Pet1 neuron subtype identities. Terminal selectors, Pet1 and Lmx1b, control chromatin accessibility in Pet1 neurons to select enhancers for 5-HT neurotransmission and synaptogenesis. In addition, these factors are required to maintain chromatin accessibility during early maturation suggesting that postmitotic open chromatin is unstable and requires continuous terminal selector input. Together our findings reveal a previously unrecognized function of terminal selectors in organizing postmitotic accessible chromatin for the development of specialized neuronal identities.

scholarly journals I-ATAC: interactive pipeline for the management and pre-processing of ATAC-seq samples

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e4040 ◽  
Author(s):  
Zeeshan Ahmed ◽  
Duygu Ucar
Keyword(s):  
Chromatin Accessibility ◽  
Clinical Samples ◽  
Open Chromatin ◽  
Data Generation ◽  
Desktop Application ◽  
Feature Based ◽  
Cross Platform ◽  
Chromatin Profiling ◽  
User Friendly ◽  
Accessible Chromatin

Assay for Transposase Accessible Chromatin (ATAC-seq) is an open chromatin profiling assay that is adapted to interrogate chromatin accessibility from small cell numbers. ATAC-seq surmounted a major technical barrier and enabled epigenome profiling of clinical samples. With this advancement in technology, we are now accumulating ATAC-seq samples from clinical samples at an unprecedented rate. These epigenomic profiles hold the key to uncovering how transcriptional programs are established in diverse human cells and are disrupted by genetic or environmental factors. Thus, the barrier to deriving important clinical insights from clinical epigenomic samples is no longer one of data generation but of data analysis. Specifically, we are still missing easy-to-use software tools that will enable non-computational scientists to analyze their own ATAC-seq samples. To facilitate systematic pre-processing and management of ATAC-seq samples, we developed an interactive, cross-platform, user-friendly and customized desktop application: interactive-ATAC (I-ATAC). I-ATAC integrates command-line data processing tools (FASTQC, Trimmomatic, BWA, Picard, ATAC_BAM_shiftrt_gappedAlign.pl, Bedtools and Macs2) into an easy-to-use platform with user interface to automatically pre-process ATAC-seq samples with parallelized and customizable pipelines. Its performance has been tested using public ATAC-seq datasets in GM12878 and CD4+T cells and a feature-based comparison is performed with some available interactive LIMS (Galaxy, SMITH, SeqBench, Wasp, NG6, openBIS). I-ATAC is designed to empower non-computational scientists to process their own datasets and to break to exclusivity of data analyses to computational scientists. Additionally, I-ATAC is capable of processing WGS and ChIP-seq samples, and can be customized by the user for one-independent or multiple-sequential operations.

scholarly journals Control of the T Follicular Helper–Germinal Center B-Cell Axis by CD8 + Regulatory T Cells Limits Atherosclerosis and Tertiary Lymphoid Organ Development

Circulation ◽  
2015 ◽  
Vol 131 (6) ◽  
pp. 560-570 ◽  
Author(s):  
Marc Clement ◽  
Kevin Guedj ◽  
Francesco Andreata ◽  
Marion Morvan ◽  
Laetitia Bey ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cell Function ◽  
Lymphoid Organs ◽  
Cell Axis ◽  
Follicular Helper ◽  
Germinal Center B Cell ◽  
Apolipoprotein E Knockout Mice

Background— The atheromodulating activity of B cells during the development of atherosclerosis is well documented, but the mechanisms by which these cells are regulated have not been investigated. Methods and Results— Here, we analyzed the contribution of Qa-1–restricted CD8 + regulatory T cells to the control of the T follicular helper–germinal center B-cell axis during atherogenesis. Genetic disruption of CD8 + regulatory T cell function in atherosclerosis-prone apolipoprotein E knockout mice resulted in overactivation of this axis in secondary lymphoid organs, led to the increased development of tertiary lymphoid organs in the aorta, and enhanced disease development. In contrast, restoring control of the T follicular helper–germinal center B-cell axis by blocking the ICOS-ICOSL pathway reduced the development of atherosclerosis and the formation of tertiary lymphoid organs. Moreover, analyses of human atherosclerotic aneurysmal arteries by flow cytometry, gene expression analysis, and immunofluorescence confirmed the presence of T follicular helper cells within tertiary lymphoid organs. Conclusions— This study is the first to demonstrate that the T follicular helper–germinal center B-cell axis is proatherogenic and that CD8 + regulatory T cells control the germinal center reaction in both secondary and tertiary lymphoid organs. Therefore, disrupting this axis represents an innovative therapeutic approach.

Human secondary lymphoid organs typically contain polyclonally-activated proliferating regulatory T cells

Blood ◽  
2013 ◽  
Vol 122 (13) ◽  
pp. 2213-2223 ◽  
Author(s):  
Jorieke H. Peters ◽  
Hans J. P. M. Koenen ◽  
Esther Fasse ◽  
Henk J. Tijssen ◽  
Jan N. M. IJzermans ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lymphoid Organs ◽  
Key Points ◽  
Secondary Lymphoid Organs

Key Points The majority of suppressive Tregs in human secondary lymphoid organs are activated, produce cytokines, and proliferate. Human lymphoid organs may provide a platform for in vivo expansion of infused Tregs and subsequent tissue-directed homing.

scholarly journals Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wolfgang Pita-Thomas ◽  
Tassia Mangetti Gonçalves ◽  
Ajeet Kumar ◽  
Guoyan Zhao ◽  
Valeria Cavalli
Keyword(s):  
Optic Nerve ◽  
Vision Loss ◽  
Axon Regeneration ◽  
Axon Growth ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Binding Motif ◽  
Open Chromatin ◽  
Transactivation Domain ◽  
Growth Capacity

AbstractRetinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote regeneration of RGC axons, we identified transcription factors (TF) and open chromatin regions that are enriched in rat embryonic RGCs (high axon growth capacity) compared to postnatal RGCs (low axon growth capacity). We found that developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the regions of the chromatin that were more accessible in embryonic RGCs. Proteomic analysis of purified rat RGC nuclei confirmed the expression of TFs with potential role in axon growth such as CREB, CTCF, YY1, and JUND. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon regeneration. Consistently, overexpression of CREB fused to the VP64 transactivation domain in mouse RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC.

scholarly journals Multi-omics analysis for potential inflammation-related genes involved in tumor immune evasion via extended application of epigenetic data

2021 ◽  
Author(s):  
Chenshen Huang ◽  
Ning Wang ◽  
Na Zhang ◽  
Zhizhan Ni ◽  
Xiaohong Liu ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Tumor Immune Evasion ◽  
Omics Analysis ◽  
Extended Application ◽  
Open Chromatin Region ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Accessible Chromatin

Background: Accumulating evidence suggests that inflammation-related genes may play key roles in tumor immune evasion. Programmed cell death ligand 1 (PD-L1) is an important immune checkpoint involved in mediating antitumor immunity. We performed multi-omics analysis to explore key inflammation-related genes affecting the transcriptional regulation of PD-L1 expression. Methods: The open chromatin region of the PD-L1 promoter was mapped using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) profiles. Correlation analysis of epigenetic data (ATAC-seq) and transcriptome data (RNA-seq) were performed to identify inflammation-related transcription factors whose expression levels were correlated with the chromatin accessibility of the PD-L1 promoter. Chromatin immunoprecipitation sequencing (ChIP-seq) profiles were used to confirm the physical binding of the TF STAT2 and the predicted binding regions. We also confirmed the results of the bioinformatics analysis with cell experiments. Results: We identified chr9:5449463-5449962 and chr9:5450250-5450749 as reproducible open chromatin regions in the PD-L1 promoter. Moreover, we observed a correlation between STAT2 expression and the accessibility of the aforementioned regions. Furthermore, we confirmed its physical binding through ChIP-seq profiles and demonstrated the regulation of PD-L1 by STAT2 overexpression in vitro. Multiple databases were also used for the validation of the results. Conclusion: Our study identified STAT2 as a direct upstream TF regulating PD-L1 expression. The interaction of STAT2 and PD-L1 might be associated with tumor immune evasion in cancers, suggesting the potential value for tumor treatment.

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