CCCTC-Binding Factor and the Transcription Factor T-bet Orchestrate T Helper 1 Cell-Specific Structure and Function at the Interferon-γ Locus

Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Immunity (Impact Factor: 21.56). 10/2009; 31(4):551-64. DOI: 10.1016/j.immuni.2009.08.021
Source: PubMed


How cell type-specific differences in chromatin conformation are achieved and their contribution to gene expression are incompletely understood. Here we identify a cryptic upstream orchestrator of interferon-gamma (IFNG) transcription, which is embedded within the human IL26 gene, compromised of a single CCCTC-binding factor (CTCF) binding site and retained in all mammals, even surviving near-complete evolutionary deletion of the equivalent gene encoding IL-26 in rodents. CTCF and cohesins occupy this element in vivo in a cell type-nonspecific manner. This element is juxtaposed to two other sites located within the first intron and downstream of Ifng, where CTCF, cohesins, and the transcription factor T-bet bind in a T helper 1 (Th1) cell-specific manner. These interactions, close proximity of other elements within the locus to each other and to the gene encoding interferon-gamma, and robust murine Ifng expression are dependent on CTCF and T-bet. The results demonstrate that cooperation between architectural (CTCF) and transcriptional enhancing (T-bet) factors and the elements to which they bind is required for proper Th1 cell-specific expression of Ifng.

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Available from: Michael Dorschner, Feb 06, 2015
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    • "It also functions as an insulator by defining the boundaries between euchromatin and heterochromatin. Three CTCF or CCCTC-binding factor sites are located across the IFNG locus and these are conserved between humans and mice (Hadjur et al., 2009; Sekimata et al., 2009). One is positioned proximal to IL26, one is located proximal to TMEVPG1 and one is located within an IFNG intron. "
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    ABSTRACT: Transcriptional activation and repression of genes that are developmentally regulated or exhibit cell-type specific expression patterns is largely achieved by modifying the chromatin template at a gene locus. Complex formation of stable epigenetic histone marks, loss or gain of DNA methylation, alterations in chromosome conformation, and specific utilization of both proximal and distal transcriptional enhancers and repressors all contribute to this process. In addition, long non-coding RNAs are a new species of regulatory RNAs that either positively or negatively regulate transcription of target gene loci. IFN-γ is a pro-inflammatory cytokine with critical functions in both innate and adaptive arms of the immune system. This review focuses on our current understanding of how the chromatin template is modified at the IFNG locus during developmental processes leading to its transcriptional activation and silencing.
    Frontiers in Immunology 05/2013; 4:112. DOI:10.3389/fimmu.2013.00112
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    • "CTCF and cohesin are both required for these interactions. The contribution of the upstream CTCF binding site suggests that the selective retention of this site, despite the deletion of the associated Il26 locus, is functionally relevant for the regulation of Ifng (Sekimata et al., 2009; Hadjur et al., 2009). Cohesin depletion is linked to disrupted promoter-enhancer interactions in embryonic stem (ES) cells (Kagey et al., 2010) and in thymocytes (Seitan et al., 2011). "
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    ABSTRACT: Current epigenomics approaches have facilitated the genome-wide identification of regulatory elements based on chromatin features and transcriptional regulator binding and have begun to map long-range interactions between regulatory elements and their targets. Here, we focus on the emerging roles of CTCF and the cohesin in coordinating long-range interactions between regulatory elements. We discuss how species-specific transposable elements may influence such interactions by remodeling the CTCF binding repertoire and suggest that cohesin's association with enhancers, promoters, and sites defined by CTCF binding has the potential to form developmentally regulated networks of long-range interactions that reflect and promote cell-type-specific transcriptional programs.
    Cell 03/2013; 152(6):1285-97. DOI:10.1016/j.cell.2013.02.029 · 32.24 Impact Factor
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    • "Indeed, a recent study (Collier et al., 2012) related the expression of NeST RNA (Tmevpg1) to the expression of IFN-g in CD4 + T cells by a mechanism that depends on the simultaneous expression of T-bet. Simultaneous binding of cohesin, T-bet, and CTCF results in a complex three-dimensional conformation that is predicted to bring the NeST and IFN-g coding regions into direct proximity (Hadjur et al., 2009; Ong and Corces, 2011; Sekimata et al., 2009). Humans express an RNA species homologous to NeST that also appears to be noncoding and is transcribed adjacent to the IFNG locus from the opposite DNA strand. "
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    ABSTRACT: Long noncoding RNAs (lncRNAs) are increasingly appreciated as regulators of cell-specific gene expression. Here, an enhancer-like lncRNA termed NeST (nettoie Salmonella pas Theiler's [cleanup Salmonella not Theiler's]) is shown to be causal for all phenotypes conferred by murine viral susceptibility locus Tmevp3. This locus was defined by crosses between SJL/J and B10.S mice and contains several candidate genes, including NeST. The SJL/J-derived locus confers higher lncRNA expression, increased interferon-γ (IFN-γ) abundance in activated CD8(+) T cells, increased Theiler's virus persistence, and decreased Salmonella enterica pathogenesis. Transgenic expression of NeST lncRNA alone was sufficient to confer all phenotypes of the SJL/J locus. NeST RNA was found to bind WDR5, a component of the histone H3 lysine 4 methyltransferase complex, and to alter histone 3 methylation at the IFN-γ locus. Thus, this lncRNA regulates epigenetic marking of IFN-γ-encoding chromatin, expression of IFN-γ, and susceptibility to a viral and a bacterial pathogen.
    Cell 02/2013; 152(4):743-54. DOI:10.1016/j.cell.2013.01.015 · 32.24 Impact Factor
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