Long-range histone acetylation of the Ifng gene is an essential feature of T cell differentiation

Abstract

Histone acetylation of promoters precedes activation of many genes. In addition, long-range histone acetylation patterns can be established over many kilobases of the chromatin of linked families of genes that are under common transcriptional control. It is not known whether establishment of long-range histone acetylation patterns is limited to gene families or is a common feature of many genes. The Ifng gene is not known to be a member of a gene family but exhibits complex strain-, cell lineage-, and stimulus-dependent regulation. For example, stimulation of naive T cells through their antigen receptor does not initiate Ifng gene transcription. However, stimulation of naive T cells through their antigen and IL-12 receptors initiates differentiation programs that yield effector cells with 100-fold greater rates of transcription of the Ifng gene after stimulation through the antigen receptor. Here, we demonstrate that these differentiation programs establish long-range histone hyperacetylation patterns that extend at least 50 kb in both upstream and downstream directions of the Ifng gene. Establishment of these histone acetylation patterns and Ifng gene expression is relatively IL-12-independent in T cells from autoimmuneprone nonobese diabetic mice. These results indicate that gene expression programs that mediate T cell differentiation are regulated by long-range histone acetylation patterns and that defective control of these patterns may contribute to development of autoimmunity.A ssembly of an active transcriptional complex at the promoter is an essential feature of eukaryotic gene expression (1-3). Histone acetylation of the promoter precedes the activation of many genes and is thought to establish a chromatin environment suitable for the assembly of the transcriptional complex (4-7). Recent evidence indicates that genes that are members of gene families, are located in relative close proximity to each other, and are regulated in a coordinated fashion exhibit long-range histone acetylation patterns that extend over many kilobases of DNA (8-11). Establishment of long-range histone acetylation patterns appears to permit communication between regulatory regions and the genes they regulate over a distance of many kilobases. In contrast, it is not known whether genes that are not members of gene families but exhibit complex forms of regulation exhibit long-range histone acetylation patterns or whether histone acetylation is limited to the promoter or gene region.Naive T cells do not efficiently transcribe the Ifng gene in response to activation of the T cell receptor. Under appropriate conditions, naive T cells will differentiate into effector T helper 1 (Th1)͞T cytotoxic 1 (Tc1) cells that transcribe the Ifng gene at 100-fold greater rates than naive T cells in response to stimulation of their antigen receptor. A limiting step in the differentiation of naive T cell precursors into effector cells that produce IFN-␥ is the requirement for both an antigen stimulus to drive cell division and an inflammatory signal ...

Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells

“…As examples, promoters of both the Ifng and Il4 genes are histone hyperacetylated during active transcription by Th1 and Th2 cells, respectively (27,28). We have investigated alterations in histone hyperacetylation along the Ifng gene region in CD8 ϩ T cells as they differentiate into effector Tc1 cells that actively transcribe the Ifng gene and effector Tc2 cells that do not actively transcribe the Ifng gene (12). The Ifng gene region acquires extensive histone acetylation across the Ϸ140-kb region both 5Ј and 3Ј of the Ϸ5-kb Ifng gene during Tc1 differentiation and active gene transcription.…”

“…Long-range, nonuniform histone hyperacetylation patterns are also formed across the Ifng gene region, a gene not known to be a member of a gene family, during the differentiation processes that lead to tissue-specific transcription in CD8 ϩ T cells (12). One question raised by these studies is whether establishment of long-range histone hyperacetylation patterns across the Ifng gene region reflects a developmental process that is necessary for active gene transcription, a nuclear signaling process that is required for efficient transcription, or both.…”

Temporal and Spatial Changes of Histone 3 K4 Dimethylation at the IFN-γ Gene during Th1 and Th2 Cell Differentiation

“…It was then maintained at high levels in Th1 cells, but gradually lost in Th2 cells. Several reported studies have examined histone modifications at the IFN-␥ gene and the Th2 cytokine gene cluster (12,20,24,(37)(38)(39)(40). These studies examined histone modifications in Th1 and Th2 cells differentiated over a short period time.…”

An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells

“…Recent published reports have suggested the existence of regulatory sequences at regions 50 kb upstream, and downstream beyond the region of IFNG itself -far more distal than what has been previously assumed. 4 In addition, histone hyperacetylation patterns and alterations in chromatin structure have been demonstrated within 24 kb of IFNG, as cells progress from naive T helper (Th) 0 to IFN-gproducing Th1 cells. 4,5 Inappropriate overexpression of IFN-g by activated mucosal T cells is an important contributory factor in the pathogenesis of inflammatory bowel disease (IBD).…”

“…4 In addition, histone hyperacetylation patterns and alterations in chromatin structure have been demonstrated within 24 kb of IFNG, as cells progress from naive T helper (Th) 0 to IFN-gproducing Th1 cells. 4,5 Inappropriate overexpression of IFN-g by activated mucosal T cells is an important contributory factor in the pathogenesis of inflammatory bowel disease (IBD). [6][7][8] In fact, disease severity is correlated with the level of IFN-g expression.…”