Chromatin structure and gene regulation in T cell development and function

Abstract

Transcription factors control gene expression programs in the context of the chromatin structure of their target genes. DNA methylation, post-translational histone modifications such as acetylation and methylation, and higher order chromatin organization allow the maintenance of gene expression patterns through mitosis, but how do they accommodate developmentally regulated changes in gene expression programs? Although histone acetylation and deacetylation are in dynamic equilibrium and mechanisms for the removal of methyl groups from histones are emerging, the extent to which there is active demethylation of DNA remains controversial. Looking at chromatin in the three-dimensional space of the nucleus, recent work demonstrates that gene regulation involves contacts between regulatory elements within genes or gene clusters on the same chromosome (in cis) and between different chromosomes (in trans). Finally, non-coding RNAs make a significant contribution to transcriptional and post-transcriptional gene silencing. Together, these advances contribute to an understanding of how gene expression programs are established, maintained and modified during development.

Figure 1

Schematic representation of chromatin modifications and intrachromosomal and interchromosomal interactions in the Th2 locus on murine chromosome 11 and in the Ifng locus on murine chromosome 10. In naïve CD4 T cells, these cytokine loci are in a poised configuration. Repressive histone modifications are limited (minimal, localized H3K27^me at the Th2 locus; there are no data regarding H327^me at the Ifng locus) or absent (H3K9^me). DNA methylation is present at distal regulatory elements in these loci but is absent from the promoter region of the Ifng gene and is present in distal but not proximal regions of the Il4 promoter. The two chromosomes interact, so that the Il5 and Ifng promoters are approximated to each other and to the RHS6 DNase HS site of the Th2 locus control region (located in the 30 end of the Rad50 gene). In Th1 and Th2 cells, the interchromosomal interactions between the Ifng locus and Th2 locus are lost. In Th1 cells, the Ifng locus acquires transcriptionally favorable histone modifications (H3/H4ac and H3K4me), the IfngCNS1 and IfngCNS2 distal regulatory elements undergo progressive DNA demethylation and acquire DNase hypersensitivity sites, and IfngCNS2 is brought into proximity to the Ifng promoter. In the Th2 locus, H3K27me and DNA methylation increase and spread upstream and downstream from the Il4 gene. Conversely, in Th2 cells changes inverse to those seen in Th1 cells occur, although there are no published data regarding H3K27me at the Ifng locus. The Rad50 gene is constitutively active in each of these cell types.