Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

61 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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. 143 RNA-seq, 83 ChIP-seq, 65 ChIP-seq controls, and 16 FAIRE-seq

ORGANISM(S): Mus musculus

SUBMITTER: Ashish Agarwal

PROVIDER: E-GEOD-40918 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

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)

2014-04-17 | E-GEOD-56019 | biostudies-arrayexpress

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

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.

2012-09-20 | GSE40918 | GEO

Distinct processes and transcriptional targets underlie CDX2 requirements in intestinal stem cells and differentiated villus cells

Project description:To define target genes of the intestine-restricted transcription factor (TF) CDX2 in intestinal stem cells, we performed chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq). We used RNA-sequencing to profile gene expression changes during cell differentiation from mouse intestinal stem cells to mature villus cells, as well as genes perturbed in intestinal stem cells upon loss of Cdx2. We find thousands of genes that change in expression during cell differentiation, including known stem cell and mature markers. Upon loss of Cdx2, hundreds of genes are up and down-regulated in intestinal stem cells, some of which are also bound by CDX2 nearby and constitute candidate direct target genes. CDX2 ChIP-Seq analysis of isolated mouse intestinal stem cells. RNA seq analysis of control mouse villus cells, control intestinal stem cells and Cdx2-deleted intestinal stem cells.

2015-09-15 | E-GEOD-70766 | biostudies-arrayexpress

BATF-JUN is critical for IRF4-mediated transcription in T cells

Project description:Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5'-GGAAnnGAAA-3'). Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4-/- T cells and IRF4 binding was diminished in Batf-/- T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription. Genome-wide transcription factors mapping and binding of IRF4, BATF, IRF8, STAT3, JUN etc in WT, Irf4-/- and Batf-/- mice in different cell types (B cells, CD4+ T cells and TH17 cells) cultured with or without IL-21 was conducted. RNA-Seq is conducted in mouse B cells, CD4+ T cells, TH1/TH2/TH9/TH17/Treg.

2012-09-18 | E-GEOD-39756 | biostudies-arrayexpress

RORγt expression in mature Th17 cells safeguard the lineage stability by inhibiting conversion to Th2 cells [RNA-Seq]

Project description:RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells and an attractive drug target for treating Th17-associated diseases. Though the critical role of RORγt in early Th17 cell differentiation has been well recognized, whether it maintains mature Th17 cell phenotypes remains largely unexplored. Here, we show that genetic deletion of Rorc in mature Th17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin structure at key Th17-specific gene loci, particularly at those so called “super enhancer” regions. Furthermore, RORc deletion in effector Th17 cells resulted in a strongly Th2-biased cell phenotype at both epigenetic and transcriptional levels, in an IL-4-dependent manner. Our results thus reveal a crucial function of RORγt in effector Th17 cells in maintaining Th17 cell program and constraining Th2 cell conversion, offering new considerations in therapeutic targeting of RORγt.

2022-07-12 | GSE190538 | GEO

RORγt expression in mature Th17 cells safeguard the lineage stability by inhibiting conversion to Th2 cells [ATAC-seq]

2022-07-12 | GSE190425 | GEO

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

Retinoic acid signaling constrains the plasticity of Th1 cells and prevents development of pathogenic Th17 cells [ChIP-Seq experiments]

Project description:CD4+ T cells differentiate into phenotypically distinct T-helper cells upon antigenic stimulation. Regulation of plasticity between these CD4+ T-cell lineages is critical for immune homeostasis and prevention of autoimmune diseases. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARa, sustains stable expression of Th1 lineage specifying genes as well as repressing genes that instruct Th17 cell fate. RA signaling is essential for limiting Th1 cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our studies identify RA-RARa as a key component of the regulatory network governing Th1 cell fate and define a new paradigm for the development of pathogenic Th17 cells. These findings have important implications for autoimmune diseases in which dysregulated Th1-Th17 responses are observed. Identification of RARa binding in wild-type Th1 cells and mapping of enhancers using chromatin IP against p300, H3k4me1, H3k4me3, and H3k27ac in wild-type and dnRara Th1 cells.

2015-03-10 | E-GEOD-60353 | biostudies-arrayexpress

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

2014-04-17 | GSE56240 | GEO