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.
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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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    • "ChIP-Seq, Repli-Seq, RNA-Seq, DHS I Mapping, and FISH Analysis ChIP-seq and RNA-Seq procedures were performed as in Yamane et al. (2011), Repli-Seq was performed as described in Hansen et al. (2010). DHSI mapping was performed as described (Sekimata et al., 2009), and fluorescence in situ hybridization (FISH) analysis is described in Callé n et al. (2007). For detailed methods, see Extended Experimental Procedures. "
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