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. 2013 May 16:4:112.
doi: 10.3389/fimmu.2013.00112. eCollection 2013.

Epigenetic Activation and Silencing of the Gene that Encodes IFN-γ

Thomas M Aune  1 , Patrick L Collins, Sarah P Collier, Melodie A Henderson, Shaojing Chang
Affiliations

Epigenetic Activation and Silencing of the Gene that Encodes IFN-γ

Thomas M Aune et al. Front Immunol. .

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.

Keywords: CpG methylation; T helper cells; epigenetics; interferon-gamma; long non-coding RNA; natural killer T cells; natural killer cells.

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Figures

Figure 1
Figure 1
Schematic illustrating transcription factors that bind to individual CNS across the IFNG locus, histone “marks” across the locus, and degree of CpG dinucleotide methylation at the different CNS in T cell and NK cell lineages.
Figure 2
Figure 2
Summary of the regulation of IFNG transcription by distal CNS at different stages of development in T cells and NK/NKT cells. Red hearts identify CNS’s that are absolutely required for IFNG transcription in the indicated cell lineage; pink hearts identify CNS’s that are partially required for IFNG transcription in the indicated cell lineage. Red lightning strikes identify CNS’s that repress IFNG transcription.
Figure 3
Figure 3
Schematic illustration of looping of chromatin domains within the IFNG locus. Changes in the three-dimensional (3-D) conformation of the IFNG locus may recruit distal conserved non-coding sequences (CNS) to the gene to regulate transcription. Distal evolutionarily conserved DNA elements are occupied by transcription factors after initiation of T helper type 1 (Th1)/Th2 differentiation programs. These transcription factors can tether enzymes that catalyze histone modifications, chromatin remodeling, and other functions to these DNA elements. Changes in three-dimensional conformation of the locus may serve to localize these DNA elements and their associated proteins to the IFNG gene. It has been argued that CTCF sites serve as boundary elements to insulate IFNG. An alternative hypothesis is that CTCF sites serve to bring IL26 close to IFNG to allow it to share the same transcriptional enhancers and to bring TMEVPG1 close to IFNG to allow TMEVPG1 RNA to associate with the IFNG locus.
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