Abstract
Combinatorial effects of epigenetic modifications on transcription activity have been proposed as “histone codes”. However, it is unclear whether there also exist inter-nucleosomal communications among epigenetic modifications at single nucleosome level, and if so, what functional roles they play. Meanwhile, how clear nucleosome patterns, such as nucleosome phasing and depletion, are formed at functional regions remains an intriguing enigma. To address these questions, we developed a Bayesian network model for interactions among different histone modifications across neighboring nucleosomes, based on the framework of dynamic Bayesian network (DBN). From this model, we found that robust inter-nucleosomal interactions exist around transcription start site (TSS), transcription termination sites (TTS) or around CTCF binding sites; and these inter-nucleosomal interactions are often involved in transcription regulation. In addition to these general principles, DBN also uncovered a novel specific epigenetic interaction between H2A.Z and H4K20me1 on neighboring nucleosomes, involved in nucleosome free region (NFR) and nucleosome phasing establishment or maintenance. The level of negative correlation between neighboring H2A.Z and H4K20me1 strongly correlate with the size of NFR and the strength of nucleosome phasing around TSS. Our study revealed inter-nucleosomal communications as important players in signal propagation, chromatin remodeling and transcription regulation.
Highlights
Epigenetic factors, such as histone modifications, are a class of important regulators of eukaryotic gene expression
Based on the inferred dynamic Bayesian network (DBN) model, we found that (1) Robust inter-nucleosome interactions exist in both orientations from the transcription start site (TSS) and CTCF center to either sides, and from termination sites (TTS) upstream to downstream; (2) Inter-nucleosome interacting histone modifications inferred by the DBN model are often known to be required for transcription regulation
The problem of learning the transition network in a DBN is reduced to learning this template BN, which can be formulated as a BN-structure learning problem under specific graph constraints (Materials and methods)
Summary
Epigenetic factors, such as histone modifications, are a class of important regulators of eukaryotic gene expression. In the initial step of gene transcription, the nucleosome in the nucleosome free region (NFR) is first evicted [2]. Several in vitro studies suggest that nucleosomes are in a dynamic equilibrium between a fully wrapped state and partial wrapped states [4, 5]. It is still unclear how the disassembly or mobility of the downstream nucleosomes is involved in the later transcription process or how histone modifications propagate across different nucleosomes. How nucleosome free region and nucleosome phasing are formed remains an enigma [6,7,8,9]
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