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Open Access Methodology article

Discovering chromatin motifs using FAIRE sequencing and the human diploid genome

Chia-Chun Yang12, Michael J Buck3, Min-Hsuan Chen2, Yun-Fan Chen2, Hsin-Chi Lan1, Jeremy JW Chen145, Chao Cheng67 and Chun-Chi Liu245*

Author Affiliations

1 Institute of Molecular Biology, National Chung Hsing University, Taiwan, ROC

2 Institute of Genomics and Bioinformatics, National Chung Hsing University, Taiwan, ROC

3 Department of Biochemistry and the Center of Excellence in Bioinformatics and Life Sciences, State University of New York, Buffalo, NY, USA

4 Institute of Biomedical Sciences, National Chung Hsing University, Taiwan, ROC

5 Agricultural Biotechnology Center, National Chung Hsing University, Taiwan, ROC

6 Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA

7 Institute for Quantitative Biomedical Sciences, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

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BMC Genomics 2013, 14:310  doi:10.1186/1471-2164-14-310

Published: 8 May 2013

Abstract

Background

Specific chromatin structures are associated with active or inactive gene transcription. The gene regulatory elements are intrinsically dynamic and alternate between inactive and active states through the recruitment of DNA binding proteins, such as chromatin-remodeling proteins.

Results

We developed a unique genome-wide method to discover DNA motifs associated with chromatin accessibility using formaldehyde-assisted isolation of regulatory elements with high-throughput sequencing (FAIRE-seq). We aligned the FAIRE-seq reads to the GM12878 diploid genome and subsequently identified differential chromatin-state regions (DCSRs) using heterozygous SNPs. The DCSR pairs represent the locations of imbalances of chromatin accessibility between alleles and are ideal to reveal chromatin motifs that may directly modulate chromatin accessibility. In this study, we used DNA 6-10mer sequences to interrogate all DCSRs, and subsequently discovered conserved chromatin motifs with significant changes in the occurrence frequency. To investigate their likely roles in biology, we studied the annotated protein associated with each of the top ten chromatin motifs genome-wide, in the intergenic regions and in genes, respectively. As a result, we found that most of these annotated motifs are associated with chromatin remodeling, reflecting their significance in biology.

Conclusions

Our method is the first one using fully phased diploid genome and FAIRE-seq to discover motifs associated with chromatin accessibility. Our results were collected to construct the first chromatin motif database (CMD), providing the potential DNA motifs recognized by chromatin-remodeling proteins and is freely available at http://syslab.nchu.edu.tw/chromatin webcite.