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Systematic investigation of multi-TLR sensing identifies novel regulators of sustained gene activation in macrophages.

ABSTRACT: Systematic investigation of multi-TLR sensing identifies novel regulators of sustained gene activation in macrophages.

PROVIDER: PRJNA354343 | ENA |

REPOSITORIES: ENA

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Systematic Investigation of Multi-TLR Sensing Identifies Regulators of Sustained Gene Activation in Macrophages.

Project description:A typical pathogen presents a combination of Toll-like receptor (TLR) ligands during infection. Although individual TLR pathways have been well characterized, the nature of this "combinatorial code" in pathogen sensing remains unclear. Here, we conducted a comprehensive transcriptomic analysis of primary macrophages stimulated with all possible pairwise combinations of four different TLR ligands to understand the requirements, kinetics, and outcome of combined pathway engagement. We find that signal integration between TLR pathways leads to non-additive responses for a subset of immune mediators with sustained expression (>6 hr) properties and T cell polarizing function. To identify the underlying regulators, we conducted a focused RNAi screen and identified four genes-Helz2, Phf11d, Sertad3, and Zscan12-which preferentially affect the late phase response of TLR-induced immune effector expression. This study reveals key molecular details of how contemporaneous signaling through multiple TLRs, as would often be the case with pathogen infection, produce biological outcomes distinct from the single ligands typically used to characterize TLR pathways.

| S-EPMC5584636 | biostudies-literature

Systematic investigation of multi-TLR sensing identifies novel regulators of sustained gene activation in macrophages.

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-08-17 | GSE89988 | GEO

Synergistic Activation of Inflammatory Cytokine Genes by Priming of Regulatory DNA Elements for Increased Transcription in Response to TLR Signaling

Project description:Synergistic activation of inflammatory cytokine genes by IFN-gamma and TLR signaling is important for innate immunity and inflammatory disease pathogenesis, but underlying mechanisms are not known. By obtaining over three billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of human primary monocytes under IFN-gamma-priming and TLR stimulation. We found that IFN-gamma induced genome-wide sustained occupancy of STAT1, IRF-1 and associated histone acetylation at TSS-proximal and distal regulatory elements and provided a synergy mechanism whereby IFN-gamma creates a primed chromatin environment to augment TLR-induced gene transcription, which suggest therapeutic approaches that selectively target priming mechanisms. Examination and comparison of the changes in TF binding and histone modification in human primary monocytes under different conditions.

2013-09-20 | E-GEOD-43036 | biostudies-arrayexpress

Systematic Discovery of TLR Signaling Components Delineates Viral-Sensing Circuits.

Project description:Chevrier N, Mertins P, Artyomov MN, Shalek AK, Iannacone M, Ciaccio MF, Gat-Viks I, Tonti E, DeGrace MM, Clauser KR, Garber M, Eisenhaure TM, Yosef N, Robinson J, Sutton A, Andersen MS, Root DE, von Andrian U, Jones RB, Park H; Carr SA, Regev A, Amit I, Hacohen N. Cell, 2011, 147(4) 853-867. doi: 10.1016/j.cell.2011.10.022. Tranche hash:HTWY5ZeSLM1hyYEyfEiJREkgLXs6BZxCczuixy9XjULsync5HCkXx/8gB7nZKpGocwOnt8vOk/Q3cpbPh/ycD/2LT0AAAAAAAAAuEg==

2013-12-10 | MSV000078507 | MassIVE

Synergistic Activation of Inflammatory Cytokine Genes by Priming of Regulatory DNA Elements for Increased Transcription in Response to TLR Signaling

2013-09-20 | GSE43036 | GEO

An in situ depot for the sustained release of a TLR7/8 agonist in combination with a TGFβ inhibitor promotes anti-tumor immune responses

Project description:The study aims to identify intratumoral TCRb CD3R diversity, number and overlap between tumors from mice carrying bilateral CT26 tumors with a treatment group being injected in one tumor (Tumor_R) with a sustained release technology providing sustained release of R848 and RepSox (CarboCell TLR:TGFb, termed CC) and not injected in the contralateral tumor (Tumor_L) compared to untreated control mice (termed UT). The Mice bearing bilateral CT26 tumors received three unilateral (Tumor_R) CarboCell TLR:TGFb injections. Tumors were harvested one week after CarboCell treatment (31 days after inoculation). Untreated tumors were harvested 17 days after inoculation. Genomic DNA was extracted and purified from tumors using the DNeasy Blood & Tissue Kit (QIAGEN) according to the manufacturer's instructions. RNA-free genomic DNA was obtained by adding 4 μl RNase A (100 mg/ml, QIAGEN). Immunosequencing of TCRβ CDR3 regions was performed using the survey ImmunoSeq Assay (Adaptive Biotechnologies, Seattle, WA). Analysis were performed to identify the shared nucleotide sequences between the treated and untreated tumors. The sample overlap was also analysed to determine the extent to which rearrangements are shared between samples using the sample overlap tool to generate a Morisita Index. The tool will compute the specified overlap measure between injected and uninfected tumor on CarboCell TLR:TGFb mice and controls.

2024-07-15 | E-MTAB-14247 | biostudies-arrayexpress

Systematic discovery of TLR signaling components delineates viral-sensing circuits.

Project description:Deciphering the signaling networks that underlie normal and disease processes remains a major challenge. Here, we report the discovery of signaling components involved in the Toll-like receptor (TLR) response of immune dendritic cells (DCs), including a previously unkown pathway shared across mammalian antiviral responses. By combining transcriptional profiling, genetic and small-molecule perturbations, and phosphoproteomics, we uncover 35 signaling regulators, including 16 known regulators, involved in TLR signaling. In particular, we find that Polo-like kinases (Plk) 2 and 4 are essential components of antiviral pathways in vitro and in vivo and activate a signaling branch involving a dozen proteins, among which is Tnfaip2, a gene associated with autoimmune diseases but whose role was unknown. Our study illustrates the power of combining systematic measurements and perturbations to elucidate complex signaling circuits and discover potential therapeutic targets.

| S-EPMC3809888 | biostudies-literature

Sustained sensing of commensal-derived products directs polarized immune cell positioning within the liver to optimize host defense

Project description:Sustained sensing of commensal-derived products directs polarized immune cell positioning within the liver to optimize host defense

| PRJNA602718 | ENA

ChIP-seq of transcription factors regulating the TLR-induced transcriptional cascades in macrophages

Project description:Toll-like receptors (TLRs) are responsible for sensing pathogen components, initiating cascades of signaling pathways, transcription factors, chromatin regulators, and activating thousands of genes contributing to diverse immune functions in macrophages. Conventional system approaches have been used to analyze TLR-induced transcriptional cascades. However, commonly used approaches possess a number of limitations, including a bias toward weakly induced genes, which are far more prevalent than strongly induced genes, and an inability to distinguish functionally important protein-DNA interactions identified by ChIP-seq from interactions that may be functionally insignificant. To develop a better understanding of a TLR-induced transcriptional cascade, we used more stringent criteria to analyze RNA-seq, ChIP-seq, and transcription factor binding motif data sets. Our analysis provided a number of insights into the regulation of an inducible transcriptional cascade. This stringent and quantitative strategy can effectively reveal gene-specific regulatory mechanisms from genome-wide studies.

2017-06-11 | GSE99895 | GEO

ChIP-seq analyses of 10 quorum sensing regulators in Pseudomonas aeruginosa

Project description:The Pseudomonas aeruginosa quorum-sensing (QS) systems contribute to bacterial homeostasis and pathogenicity. Although many regulators have been characterized to control the production of virulence factors and QS signaling molecules, its detailed regulatory mechanisms still remain elusive. Here, we performed chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-seq) on 10 key QS regulators. The direct regulation of these genes by corresponding regulator has been confirmed by Electrophoretic mobility shift assays (EMSAs) and quantitative real-time polymerase chain reactions (qRT-PCR). Binding motifs are found by using MEME suite and verified by footprint assays in vitro. Collectively, this work provides new cues to better understand the detailed regulatory networks of QS systems. ChIP-seq of 10 QS regulators in Pseudomonas aeruginosa

2015-08-04 | E-GEOD-65356 | biostudies-arrayexpress

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