Epigenetics and T helper 1 differentiation - PubMed (original) (raw)

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Epigenetics and T helper 1 differentiation

Thomas M Aune et al. Immunology. 2009 Mar.

Abstract

Naïve T helper cells differentiate into two subsets, T helper 1 and 2, which either transcribe the Ifng gene and silence the Il4 gene or transcribe the Il4 gene and silence the Ifng gene, respectively. This process is an essential feature of the adaptive immune response to a pathogen and the development of long-lasting immunity. The 'histone code' hypothesis proposes that formation of stable epigenetic histone marks at a gene locus that activate or repress transcription is essential for cell fate determinations, such as T helper 1/T helper 2 cell fate decisions. Activation and silencing of the Ifng gene are achieved through the creation of stable epigenetic histone marks spanning a region of genomic DNA over 20 times greater than the gene itself. Key transcription factors that drive the T helper 1 lineage decision, signal transducer and activator 4 (STAT4) and T-box expressed in T cells (T-bet), play direct roles in the formation of activating histone marks at the Ifng locus. Conversely, STAT6 and GATA binding protein 3, transcription factors essential for the T helper 2 cell lineage decision, establish repressive histone marks at the Ifng locus. Functional studies demonstrate that multiple genomic elements up to 50 kilobases from Ifng play critical roles in its proper transcriptional regulation. Studies of three-dimensional chromatin conformation indicate that these distal regulatory elements may loop towards Ifng to regulate its transcription. We speculate that these complex mechanisms have evolved to tightly control levels of interferon-gamma production, given that too little or too much production would be very deleterious to the host.

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Figures

Figure 1

Figure 1

The Ifng locus. (a) Schematic and functional properties of two human IFNG transgenes. The upper transgene is an ∼8·6 kilobase (kb) fragment containing the human IFNG gene and 2·0–2·5 of upstream and downstream sequence. The lower transgene is an ∼190 kb bacterial artificial chromosome with the human IFNG gene and flanking sequence. (b) Positions of evolutionarily conserved non-coding DNA elements relative to the Ifng gene from the dcode website (

http://www.dcode.org

). (c) Positions of conserved non-coding sequences (CNS), filled circles, relative to the mouse (upper) and human (lower) Ifng/IFNG genes. Lines connect representative individual CNS within the mouse and human loci.

Figure 2

Figure 2

Kinetics of histone modifications at the Ifng locus during T helper 1 (Th1)/Th2 differentiation. Initiation of Th1 and Th2 differentiation programmes induces formation of markedly different histone ‘marks’ at the Ifng locus. Both signal transducer and activator 4 (STAT4) and T-box expressed in T cells (T-bet) play critical roles in directing the formation of histone 4 (H4)-acetylation marks in developing Th1 cells and STAT6 and GATA-binding protein 3 (GATA-3) play critical roles in directing the formation of H3K27-methylation marks in developing Th2 cells. Changes in H3K9-methylation marks during differentiation illustrate the dynamic nature of the histone code in developing effector T cells.

Figure 3

Figure 3

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 (TF) after initiation of T helper type 1 (Th1)/Th2 differentiation programmes. These transcription factors can tether enzymes that catalyse histone modifications, chromatin remodelling 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. CNS, conserved non-coding sequences.

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