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Open Access Research

Whole-genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation

Shaoke Lou12, Heung-Man Lee345, Hao Qin2, Jing-Woei Li2, Zhibo Gao6, Xin Liu6, Landon L Chan12, Vincent KL Lam345, Wing-Yee So345, Ying Wang345, Si Lok7, Jun Wang10689, Ronald CW Ma345, Stephen Kwok-Wing Tsui111213, Juliana CN Chan345*, Ting-Fung Chan12132* and Kevin Y Yip112134*

Author Affiliations

1 Department of Computer Science and Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

2 School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

3 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

4 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

5 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

6 Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China

7 Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

8 Department of Biology, University of Copenhagen, Copenhagen, Denmark

9 The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

10 King Abdulaziz University, Jeddah, Saudi Arabia

11 School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

12 Hong Kong Bioinformatics Centre, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

13 CUHK-BGI Innovation Institute of Trans-omics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

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Genome Biology 2014, 15:408  doi:10.1186/s13059-014-0408-0

Published: 30 July 2014

Abstract

Background

DNA methylation is an important type of epigenetic modification involved in gene regulation. Although strong DNA methylation at promoters is widely recognized to be associated with transcriptional repression, many aspects of DNA methylation remain not fully understood, including the quantitative relationships between DNA methylation and expression levels, and the individual roles of promoter and gene body methylation.

Results

Here we present an integrated analysis of whole-genome bisulfite sequencing and RNA sequencing data from human samples and cell lines. We find that while promoter methylation inversely correlates with gene expression as generally observed, the repressive effect is clear only on genes with a very high DNA methylation level. By means of statistical modeling, we find that DNA methylation is indicative of the expression class of a gene in general, but gene body methylation is a better indicator than promoter methylation. These findings are general in that a model constructed from a sample or cell line could accurately fit the unseen data from another. We further find that promoter and gene body methylation have minimal redundancy, and either one is sufficient to signify low expression. Finally, we obtain increased modeling power by integrating histone modification data with the DNA methylation data, showing that neither type of information fully subsumes the other.

Conclusion

Our results suggest that DNA methylation outside promoters also plays critical roles in gene regulation. Future studies on gene regulatory mechanisms and disease-associated differential methylation should pay more attention to DNA methylation at gene bodies and other non-promoter regions.