Abstract
BackgroundGene promoters in vertebrate genomes show distinct chromatin features such as stably positioned nucleosome array and DNA hypomethylation. The nucleosomes are known to have certain sequence preferences, and the prediction of nucleosome positioning from DNA sequence has been successful in some organisms such as yeast. However, at gene promoters where nucleosomes are much more stably positioned than in other regions, the sequence-based model has failed to work well, and sequence-independent mechanisms have been proposed.ResultsUsing DNase I-seq in medaka embryos, we demonstrated that hypomethylated domains (HMDs) specifically possess accessible nucleosome organization with longer linkers, and we reassessed the DNA sequence preference for nucleosome positioning in these specific regions. Remarkably, we found with a supervised machine learning algorithm, k-mer SVM, that nucleosome positioning in HMDs is accurately predictable from DNA sequence alone. Specific short sequences (6-mers) that contribute to the prediction are specifically enriched in HMDs and distribute periodically with approximately 200-bp intervals which prepattern the position of accessible linkers. Surprisingly, the sequence preference of the nucleosome and linker in HMDs is opposite from that reported previously. Furthermore, the periodicity of specific motifs at hypomethylated promoters was conserved in zebrafish.ConclusionThis study reveals strong link between nucleosome positioning and DNA sequence at vertebrate promoters, and we propose hypomethylated DNA-specific regulation of nucleosome positioning.
Highlights
Gene promoters in vertebrate genomes show distinct chromatin features such as stably positioned nucleosome array and DNA hypomethylation
hypomethylated domains (HMDs) have specific nucleosome organization We previously reported 15,145 HMDs containing at least 10 continuous low-methylated CpGs in the genome of medaka blastula embryos, and the majority (69%) of the HMDs are found in gene promoter regions [23]
323 million reads generated by DNase I digestions were mapped to the medaka reference genome and 36,375 DNase I hypersensitive sites (DHSs) were identified using MACS2 software [29] by searching regions with significant enrichment (FDR < 0.1%, fold enrichment > 5) of DNase I cleavage
Summary
Gene promoters in vertebrate genomes show distinct chromatin features such as stably positioned nucleosome array and DNA hypomethylation. The nucleosomes are known to have certain sequence preferences, and the prediction of nucleosome positioning from DNA sequence has been successful in some organisms such as yeast. At gene promoters where nucleosomes are much more stably positioned than in other regions, the sequence-based model has failed to work well, and sequence-independent mechanisms have been proposed. Eukaryotic genomes are organized into chromatin, a DNA–protein complex, together with epigenetic information such as nucleosome position, histone modification, and DNA methylation. Positioning of nucleosomes affects accessibility of regulatory proteins to DNA and thereby influences gene transcription [2]. Using generation sequencing techniques, many studies have attempted to identify the basic principle for nucleosome positioning and have found that nucleosomes have DNA sequence preference. Genome-wide nucleosome mapping in yeast and C. elegans revealed that the position of nucleosomes on the genome is accurately predictable from
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