Genome-wide prediction of conserved and nonconserved enhancers by histone acetylation patterns

Abstract

Comparative genomic studies have been useful in identifying transcriptional regulatory elements in higher eukaryotic genomes, but many important regulatory elements cannot be detected by such analyses due to evolutionary variations and alignment tool limitations. Therefore, in this study we exploit the highly conserved nature of epigenetic modifications to identify potential transcriptional enhancers. By using a high-resolution genome-wide mapping technique, which combines the chromatin immunoprecipitation and serial analysis of gene expression assays, we have recently determined the distribution of lysine 9/14-diacetylated histone H3 in human T cells. We showed the existence of 46,813 regions with clusters of histone acetylation, termed histone acetylation islands, some of which correspond to known transcriptional regulatory elements. In the present study, we find that 4679 sequences conserved between human and pufferfish coincide with histone acetylation islands, and random sampling shows that 33% (13/39) of these can function as transcriptional enhancers in human Jurkat T cells. In addition, by comparing the human histone acetylation island sequences with mouse genome sequences, we find that despite the conservation of many of these regions between these species, 21,855 of these sequences are not conserved. Furthermore, we demonstrate that about 50% (26/51) of these nonconserved sequences have enhancer activity in Jurkat cells, and that many of the orthologous mouse sequences also have enhancer activity in addition to conserved epigenetic modification patterns in mouse T-cell chromatin. Therefore, by combining epigenetic modification and sequence data, we have established a novel genome-wide method for identifying regulatory elements not discernable by comparative genomics alone.

PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale

“…H3K9Ac, which is a well-documented signature of enhancers (Roh et al 2007), was markedly enriched in the vicinity of PPAR␥ binding (Fig. 1C).…”

Histone Modifications Are Associated with Δ9-Tetrahydrocannabinol-mediated Alterations in Antigen-specific T Cell Responses

“…However, H3K4me3 and H3K27me3 that seem to be associated with opposite functions can co-exist in the same regions. This so-called "bivalent domain" has been found in embryonic stem cells and T cells and are proposed to lead to activation or suppression (23)(24)(25). Histone lysine 36 trimethylation (H3K36me3) has been linked to transcription elongation and is enriched in the body of active transcripts (26,27).…”

An Evolutionarily Conserved TNF-α–Responsive Enhancer in the Far Upstream Region of Human CCL2 Locus Influences Its Gene Expression

“…BAC, BAC clone containing CCL2 locus; NTC, no template control. and establishment of a transcriptionally primed epigenetic state (17,53,(68)(69)(70)(71). Such regions are often referred to as locus control regions (LCRs).…”

“…Such regulatory elements 1) are typically composed of long stretches of noncoding nucleotides (.100 bp) that share a high degree of homology between different species (.70%) and may exhibit functional conservation of TF binding sites; 2) display increased susceptibility to nuclease digestion and undergo epigenetic changes such as demethylation and altered histone patterns that are associated with gene expression (17); and 3) may directly interact with proximal promoters, and such DNA-DNA interactions may be important for optimal gene expression (18)(19)(20)(21). Recent availability of wholegenome sequences from several mammalian species has provided a tremendous resource for identification and characterization of such novel regulatory elements.…”