Given the distinct chromatin states that govern specific regions of the genome, it is likely that genes with comparable transcription profiles possess similar epigenetic landscapes. Genome-wide studies in human T cells have extensively characterized a large number of histone modifications using chromatin immunoprecipitation assays (ChIP) combined with massively parallel sequencing (ChIP-Seq) and have been particularly informative in identifying modification patterns associated with active and inactive genes.[34-38, 46, 47] In general, promoters with an active chromatin signature have intermediate to high gene expression levels but genes with low expression levels are associated with promoters with repressed chromatin signatures. A major study focusing on 37 histone acetylation and methylation marks in human CD4+ T cells has shown that genes with different basal expression levels are associated with specific combinations of histone modifications. A common backbone of histone modifications consisting of: histone variant H2A.Z, H2BK5ac, H2BK12ac, H2BK20ac, H2BK120ac, H3K4ac, H3K4me1, H3K4me2, H3K4me3, H3K9me1, H3K18ac, H3K27ac, H3K36ac, H4K5ac, H4K8ac, H4K91ac and H3K9ac was identified at a large number of promoters and tended to correlate with higher expression levels. Complimentary human T-cell ChIP-Seq data revealed that a similar chromatin signature marks not only active genes but also inducible genes, and the enrichment of these marks distinguishes them from their non-responsive counterparts with similar basal expression levels, especially in the lower basal expression group. In general, active genes have H3K4me1/2/3, H3K9me1 and H3 acetylation at the promoter region and H2BK5me1, H3K9me2/3, H3K27me1, H3K36me3, H3K27me1 and H4K20me1 distributed throughout transcribed regions.[34, 38, 39, 47, 49] Conversely, inactive genes are enriched with high levels of H3K9me2/3, H3K27me3 and H3K79me3 but low levels of H3K9me1, H3K27me1, H3K36me3, H4K20me1 and H3K4me.[34, 47, 50, 51] Bivalent promoters (having both H3K4me3 and H3K27me3) are also present in T cells though not to the same extent as in embryonic stem cells.[35, 47, 52-54] Poised genes are generally indicated by the active markers like H3K9ac and H3K4me3 but not the repressive methylation marker, H3K27me3 at the promoter in the resting state (summarized in Fig. 2).[35, 38, 47, 48] This chromatin signature does not change upon gene activation, suggesting that these genes may have a chromatin structure that is epigenetically primed for activation.[48, 55, 56] This was unexpected as haematopoietic stem cells show dynamic changes in chromatin structure upon differentiation. The discrepancy in these results could indicate that the chromatin structure of inducible genes is set up before gene transcription and this feature is unique to T cells.[48, 55, 56] Having a similar chromatin signature may help in co-ordinating and co-regulating transcriptional events for efficient and rapid activation of genes.
The active chromatin acetylation signature has recently been proposed to be maintained by constitutive transcription factors such as Sp1 recruiting histone acetylases, such as p300, to promoters of primary response genes. Upon induction, inducible transcription factors such as nuclear factor-κB recruit distinct acetylases that modify a set of lysines, specifically H4K5/8/12, to generate optimal gene activation. Genome-wide mapping of HATs and HDACs in human CD4+ T cells has shown that transcriptionally silent genes with H3K4me3 are primed for future activation by the cycling of transient acetylation by HATs and deacetylation by HDACs. During T-cell activation, elongating phosphorylated Pol II recruits both HATs and HDACs to the transcribed regions of active genes that alter the acetylation levels within the transcribed region to facilitate transcriptional elongation. Indeed, acetylation increases within the transcribed region of the highly inducible IL2 gene upon T-cell activation. It would be of great interest to examine the involvement of HATs and HDACs with other histone modifications in inducible genes specific to T cells.
The active chromatin state detected in the resting state of inducible genes could be a result of past transcriptional activity. Indeed, the active histone modifications of constitutively active genes were shown to be retained through cell division. This could explain how inducible genes acquire active chromatin signature, so enabling a fast and effective transcription of these genes in daughter cells. For example, genes encoding signalling molecules have a repressive chromatin state in naive T cells but a permissive chromatin state in memory T cells, hence these genes in memory T cells are able to respond more quickly to T-cell activation. Furthermore, gene promoters in memory T cells have increased histone acetylation levels when compared with naive T cells. Increased acetylation levels were retained even after numerous cell divisions.[62, 63] There is currently intense interest in determining the mechanisms responsible for the inheritance of permissive chromatin states in memory T cells, as this is an essential step in mediating a faster gene expression response that is required to combat re-infection.