Dissecting Nucleosome Free Regions by a Segmental Semi-Markov Model

Wei Sun,Michael Grunstein,Feng Xu,Ker-Chau Li,Wei Xie

doi:10.1371/journal.pone.0004721

Abstract

BackgroundNucleosome free regions (NFRs) play important roles in diverse biological processes including gene regulation. A genome-wide quantitative portrait of each individual NFR, with their starting and ending positions, lengths, and degrees of nucleosome depletion is critical for revealing the heterogeneity of gene regulation and chromatin organization. By averaging nucleosome occupancy levels, previous studies have identified the presence of NFRs in the promoter regions across many genes. However, evaluation of the quantitative characteristics of individual NFRs requires an NFR calling method.MethodologyIn this study, we propose a statistical method to identify the patterns of NFRs from a genome-wide measurement of nucleosome occupancy. This method is based on an appropriately designed segmental semi-Markov model, which can capture each NFR pattern and output its quantitative characterizations. Our results show that the majority of the NFRs are located in intergenic regions or promoters with a length of about 400–600bp and varying degrees of nucleosome depletion. Our quantitative NFR mapping allows for an investigation of the relative impacts of transcription machinery and DNA sequence in evicting histones from NFRs. We show that while both factors have significant overall effects, their specific contributions vary across different subtypes of NFRs.ConclusionThe emphasis of our approach on the variation rather than the consensus of nucleosome free regions sets the tone for enabling the exploration of many subtler dynamic aspects of chromatin biology.

Highlights

Nucleosomes, the building blocks of chromatin, are critical regulators in many biological processes, such as transcription, DNA repair and replication [1]
The emphasis of our approach on the variation rather than the consensus of nucleosome free regions sets the tone for enabling the exploration of many subtler dynamic aspects of chromatin biology
Nucleosome free regions (NFRs) identification by SSMM In order to examine individual NFR across the whole genome, we developed an automatic ‘‘NFR calling’’ algorithm based on a segmental semi-Markov model (SSMM) to capture the quantitative properties of each NFR

Summary

Introduction

Nucleosomes, the building blocks of chromatin, are critical regulators in many biological processes, such as transcription, DNA repair and replication [1]. Despite the availability of genome wide nucleosome distribution profiles, several fundamental questions regarding the nature of nucleosome free regions (NFRs) remain unknown. It is not clear whether NFRs occur exclusively at the promoter regions. The transcriptional machinery and DNA sequence have been shown to be involved in histone eviction [9,10,11], they may have distinct effects for different subtypes of NFRs. Nucleosome free regions (NFRs) play important roles in diverse biological processes including gene regulation. A genome-wide quantitative portrait of each individual NFR, with their starting and ending positions, lengths, and degrees of nucleosome depletion is critical for revealing the heterogeneity of gene regulation and chromatin organization. Evaluation of the quantitative characteristics of individual NFRs requires an NFR calling method

Methods

Results

Conclusion