Genome-wide analysis of the relationships between DNaseI HS, histone modifications and gene expression reveals distinct modes of chromatin domains

Abstract

To understand the molecular mechanisms that underlie global transcriptional regulation, it is essential to first identify all the transcriptional regulatory elements in the human genome. The advent of next-generation sequencing has provided a powerful platform for genome-wide analysis of different species and specific cell types; when combined with traditional techniques to identify regions of open chromatin [DNaseI hypersensitivity (DHS)] or specific binding locations of transcription factors [chromatin immunoprecipitation (ChIP)], and expression data from microarrays, we become uniquely poised to uncover the mysteries of the genome and its regulation. To this end, we have performed global meta-analysis of the relationship among data from DNaseI-seq, ChIP-seq and expression arrays, and found that specific correlations exist among regulatory elements and gene expression across different cell types. These correlations revealed four distinct modes of chromatin domain structure reflecting different functions: repressive, active, primed and bivalent. Furthermore, CCCTC-binding factor (CTCF) binding sites were identified based on these integrative data. Our findings uncovered a complex regulatory process involving by DNaseI HS sites and histone modifications, and suggest that these dynamic elements may be responsible for maintaining chromatin structure and integrity of the human genome. Our integrative approach provides an example by which data from diverse technology platforms may be integrated to provide more meaningful insights into global transcriptional regulation.

Targeting H3K4 trimethylation in Huntington disease

“…For example, in Arabidopsis, genes with expression patterns that are altered in response to dehydration show a pattern of H3K4me3 at transcriptional start sites similar to the one that we observe for down-regulated HD genes, and this pattern persists in both the dehydrated and watered state (26). The H3K4me3 classes that we observe also closely resemble the clusters previously reported for H3K4me2 in human CD4+ T cells (27). In this case, genes with tissue-specific expression showed a broader distribution of the mark extending into the expressed portion of the gene, suggesting that a unique chromatin signature at specific promoters may regulate their tissue-specific expression.…”

“…We used sequence analysis to identify potential transcriptional regulators that could be recruiting methyltransferases and demethylases to differentially expressed genes in R6/2 mice. Previous studies (24,27) have shown that the sites of such regulators should not be expected directly underneath the peaks of methylation. Therefore, we determined the location of chromatin accessible binding sites for regulatory proteins near the enriched H3K4me3 regions in WT and R6/2 mice based on an empirical spatial distribution derived from DNase-Seq and H3K4me3 ChIP-Seq data (Fig.…”

Comparative genome-wide DNA methylation analysis of colorectal tumor and matched normal tissues

“…5A). 24,25 This is confirmed with a comparison of peak tracks of H3K4me3 and H3K27me3 in H1 cells data sets (GSE25070 and GSE21815) were mined. 5,27 The first data set consists of transcript levels of 26 CRC and 26 matched normal colon tissues obtained with Illumina beadchips.…”

Massively parallel cis-regulatory analysis in the mammalian central nervous system

“…Almost all of the DHS regions fell within introns (46%) or intergenic regions (45%) (Supplemental Fig. S1B), similar to the genome-wide distribution of DHS regions in other cell types (Shu et al 2011). A small number of DHSs (156/4000 or 4%) were "promoter-proximal," i.e., falling within −1 kb to +100 bp relative to the nearest TSS (Supplemental Fig.…”