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A validated regulatory network for Th17 cell specification

ABSTRACT: Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively-bound BATF and IRF4 contribute to initial chromatin accessibility, and with STAT3 initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple datasets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE40918 | GEO | 2012/09/20

SECONDARY ACCESSION(S): PRJNA175364

REPOSITORIES: GEO

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A validated regulatory network for Th17 cell specification

Project description:Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively-bound BATF and IRF4 contribute to initial chromatin accessibility, and with STAT3 initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple datasets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease. 143 RNA-seq, 83 ChIP-seq, 65 ChIP-seq controls, and 16 FAIRE-seq

2012-09-20 | E-GEOD-40918 | biostudies-arrayexpress

Mapping interactome networks of FOSL1 and FOSL2 in human Th17 cells

Project description:The differentiation of Th17 cells is controlled by a complex network of transcription factors (TFs), including FOS and JUN proteins of the AP-1 family. The FOS-like proteins, FOSL1 and FOSL2 have recently been reported to control Th17 responses. The molecular mechanisms dictating their roles, however, are unclear. Moreover, although the functions of AP-1 TFs are largely governed by their protein-protein interactions, these are also poorly characterized in this milieu. Using affinity purification in combination with mass-spectrometry we established the first interactomes of FOSL1 and FOSL2 in human Th17 cells. In addition to their known interactions with JUN proteins, our analysis identified several novel binding partners of FOSL factors. Gene ontology analysis revealed RNA binding was enriched as the major functionality for FOSL1 and FOSL2 associated proteins, thereby suggesting possible mechanistic links that have not been studied before. Intriguingly, 29 interactors were found to be shared between FOSL1 and FOSL2, which included crucial regulators of Th17-fate. These findings, including unique and shared interactions, were validated using parallel reaction monitoring targeted mass-spectrometry (PRM-MS), with additional measurements with other laboratory methods. Overall, this study provides key insights into interaction-based signalling mechanisms of FOSL1 and FOSL2, which potentially control Th17 cell-development and associated pathologies.

2021-11-02 | PXD025729 | Pride

Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [ChIP-Seq]

Project description:RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. DNA binding of RORγt in WT Th17 cells and under chemical perturbations of RORγt; Additional data is included for epitope-tagged exogenous RORγt in EL4 cells (a murine lymphoma cell line)

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Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [RNA-Seq 2]

Project description:RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Transcriptional profiling of Th17 cells under chemical perturbations of RORγt, DMSO, and knockout of RORγt. It includes repeats for all the data in GSE56018, plus one additional condition.

2014-04-17 | E-GEOD-56240 | biostudies-arrayexpress

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Project description:The aim of this study was to investigate the transciptional mechanisms governed by FOSL1, FOSL2 and BATF for regulation of human Th17 cell-function. To determine the genome-wide binding sites of these factors, ChIP-seq analysis was performed using in vitro derived Th17 cells at 72h of polarization.

2022-04-12 | GSE174810 | GEO

Global gene-regulatory targets of FOSL1, FOSL2 and BATF in human Th17 cells [RNA-seq]

Project description:The aim of this study was to investigate the transciptional mechanisms governed by FOSL1, FOSL2 and BATF for regulation of human Th17 cell-function. FOSL factors were transiently perturbed using RNAi (KD) and over-expression (OE) strategies, whereas BATF was perturbed using RNAi only. RNA-seq was then performed to determine their global transciptional targets.

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Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [RNA-Seq 2]

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Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [ChIP-Seq]

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Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [RNA-Seq]

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The Swi/Snf chromatin remodeling complex promotes Th17 differentiation by coordinating RORγt-driven epigenetic program

Project description:TH17 cells play a critical role in mucosal immunity and also in multiple autoimmune diseases. The differentiation of TH17 cells is dictated by a master transcription factor, RORγt; however, the mechanism by which RORγt controls target genes is poorly understood. Here we identify the Swi/Snf chromatin remodeling complex as an essential regulator of TH17 cell differentiation. Loss of the expression of SRG3/mBAF155, a core subunit of the Swi/Snf complex, results in a specific downregulation of RORγt target genes such as IL-17A, IL-17F and IL-23R. Importantly, the comparative transcriptional analysis reveals a high similarity between RORγt and the Swi/Snf complex in the control of TH17-related gene expression. Mechanistically, the Swi/Snf complex partners with RORγt and coordinates a variety of RORγt–mediated epigenetic modifications, including both permissive and repressive ones. These results provide a basis for the understanding of how a master transcription factor RORγt cooperates with the Swi/Snf complex to govern the Th17 cell differentiation.

2020-05-06 | GSE129132 | GEO

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