Abstract
Four different histones (H2A, H2B, H3, and H4; two subunits each) constitute a histone octamer, around which DNA wraps to form histone-DNA complexes called nucleosomes. Amino acid residues in each histone are occasionally modified, resulting in several biological effects, including differential regulation of transcription. Core promoters that encompass the transcription start site have well-conserved DNA motifs, including the initiator (Inr), TATA box, and DPE, which are collectively called the core promoter elements (CPEs). In this study, we systematically studied the associations between the CPEs and histone modifications by integrating the Drosophila Core Promoter Database and time-series ChIP-seq data for histone modifications (H3K4me3, H3K27ac, and H3K27me3) during development in Drosophila melanogaster via the modENCODE project. We classified 96 core promoters into four groups based on the presence or absence of the TATA box or DPE, calculated the histone modification ratio at the core promoter region, and transcribed region for each core promoter. We found that the histone modifications in TATA-less groups were static during development and that the core promoters could be clearly divided into three types: i) core promoters with continuous active marks (H3K4me3 and H3K27ac), ii) core promoters with a continuous inactive mark (H3K27me3) and occasional active marks, and iii) core promoters with occasional histone modifications. Linear regression analysis and non-linear regression by random forest showed that the TATA-containing groups included core promoters without histone modifications, for which the measured RNA expression values were not predictable accurately from the histone modification status. DPE-containing groups had a higher relative frequency of H3K27me3 in both the core promoter region and transcribed region. In summary, our analysis showed that there was a systematic link between the existence of the CPEs and the dynamics, frequency and influence on transcriptional activity of histone modifications.
Highlights
As massively parallel DNA sequencing by next-generation sequencing (NGS) is gaining popularity, biologists have gained better access to genome-wide analysis using NGS-based techniques such as chromatin immunoprecipitation (ChIP)-seq or RNA-seq
We found that promoters with different combination of core promoter elements (CPEs) had different patterns in the dynamics, transcriptional influence, and frequency of histone modifications
Benveniste et al reported that histone modifications could be predicted from TF-binding data with high accuracy and suggested that an indirect effect of interactions between TFs and chromatin-modifying enzymes as well as a direct effect of these enzymes could explain the relationship between the pattern of histone modification and gene expression [14]
Summary
As massively parallel DNA sequencing by next-generation sequencing (NGS) is gaining popularity, biologists have gained better access to genome-wide analysis using NGS-based techniques such as chromatin immunoprecipitation (ChIP)-seq (the combination of ChIP and NGS to determine the locus at which a protein of interest is bound) or RNA-seq (quantitative detection of transcripts by NGS). The enhancement of biological databases has been made possible through the efforts of scientists involved in large-scale projects such as the modENCODE project [1]. This project aims to “identify all of the sequence-based functional elements” in model animals, including Drosophila melanogaster. For this purpose, researchers have collected comprehensive data, including RNA-seq for transcripts and ChIP-seq for modified histones, under different experimental conditions. A variety of histone modifications have been reported to date, including lysine acetylation, lysine methylation, arginine methylation, serine phosphorylation, and lysine ubiquitylation [3]. The biological functions and molecular mechanisms of these histone modifications have been the focus of many recent investigations, few studies have examined the functions of histone modifications in a dynamic system, such as development
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