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Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation (ChIP-Seq)

ABSTRACT: Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper specification.

ORGANISM(S): Mus musculus

PROVIDER: GSE22104 | GEO | 2010/06/18

SECONDARY ACCESSION(S): PRJNA129179

REPOSITORIES: GEO

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Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation (ChIP-Seq)

Project description:Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper specification. The roles of STAT proteins to shape T helper cell phenotype was investigated by comparing DNA binding profiles of STAT4 and STAT6 in Th1 and Th2 conditions. The functional outcome of STAT bindings was further evaluated by profiling histone epigenetic marks and gene expression changes between WT and STAT-deficient T cells in Th1 and Th2 conditions.

2010-06-18 | E-GEOD-22104 | biostudies-arrayexpress

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Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation

Project description:This SuperSeries is composed of the following subset Series: GSE22081: Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation (gene expression) GSE22104: Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation (ChIP-Seq) Refer to individual Series

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Project description:Follicular helper T (Tfh) cells comprise an important subset of helper T cells; however, their relationship with other helper lineages is incompletely understood. Herein, we show IL-12 acting via signal transducer and activator of transcription 4 (STAT4) induced both Il21 and Bcl6 genes, generating cells with features of both Tfh and Th1 cells. However, STAT4 also induced T-bet. Using ChIP-seq, we defined the genome-wide targets of T-bet and found that it repressed Bcl6 and other markers of Tfh cells, thereby attenuating the nascent Tfh-like phenotype in the late phase of Th1 specification. Finally, Tfh-like T cells were rapidly generated following Toxoplasma gondii infection in mice, but T-bet constrained Tfh cells expansion and consequent germinal center formation and antibody production. Our data argue that Tfh and Th1 share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh functionalities, promoting full Th1 differentiation. The roles of STAT4 and T-bet to determine T helper cell fate were investigated by comparing DNA binding profiles of STAT4 and T-bet in Th1 conditions. The functional outcome was further evaluated by profiling DNase hypersensitivity sites and histone epigenetic marks between WT and STAT4-deficient or T-bet-deficient T cells in Th1 conditions.

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Project description:Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation

| PRJNA128909 | ENA

Mus musculus

Project description:Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation (ChIP-Seq)

| PRJNA129179 | ENA

Mus musculus

Project description:Discrete Roles of STAT4 and STAT6 Transcription Factors in Tuning Epigenetic Modifications and Transcription during Helper T Cell Differentiation (gene expression)

| PRJNA129181 | ENA

Expression and regulation of lincRNAs during T cell development and differentiation

Project description:Although lincRNAs are implicated in regulating gene expression in various tissues, little is known about lincRNA transcriptomes in the T cell lineages. Here we identify 1,524 lincRNAs in 42 T cell samples from early T cell progenitors to terminally differentiated T helper subsets. Our analysis revealed highly dynamic and cell-specific expression patterns of lincRNAs during T cell differentiation. Importantly, these lincRNAs are located in genomic regions enriched for protein-coding genes with immune-regulatory functions. Many of these transcripts are bound and regulated by the key T cell transcription factors, T-bet, GATA3, STAT4 and STAT6. We demonstrate that the lincRNA LincR-Ccr2-5'AS, together with GATA3, is an essential component of a regulatory circuit in Th2-specific gene expression. To obtain comprehensive profiles of lincRNA expression during the development and differentiation of T cell lineages, we purified CD4-CD8 double negative (DN) cells (DN1, DN2, DN3 and DN4), double positive (DP) cells (CD4+CD8+CD3low and CD4+CD8intCD69+), single positive (SP) CD4 and CD8 cells, and thymic-derived regulatory T cells (tTreg) from thymi of C57BL/6 mice. Additionally, we obtained Th1, Th2, Th17 and iTreg cells by in vitro differentiation of naM-CM-/ve CD4 T cells for a various length of time in culture (4 hrs, 8 hrs, 12 hrs, 24 hrs, 48 hrs, 72 hrs, 1 week, 2weeks). Total and/or polyadenylated RNAs from these cells was analyzed using RNA-Seq. To understand the regulation of lincRNAs by T cell master regulator T-bet, we compared the transcriptiomes between T-bet deficient Th1 cells and control Th1 cells. We did similar experiments and data analysis for STAT4 (Th1), GATA3 (Th2) and STAT6 (Th2). Finally, to address the funcation of a Th2-specifically expressed lincRNA, lincR-Ccr2-5'AS, we compared the transcriptomes between lincR-Ccr2-5'AS knockdown Th2 cells and control Th2 cells.

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