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Classification of human genomic regions based on experimentally determined binding sites of more than 100 transcription-related factors

Kevin Y Yip12345, Chao Cheng12, Nitin Bhardwaj12, James B Brown6, Jing Leng1, Anshul Kundaje7, Joel Rozowsky12, Ewan Birney8, Peter Bickel6, Michael Snyder9 and Mark Gerstein1102*

Author affiliations

1 Program in Computational Biology and Bioinformatics, Yale University, 260 Whitney Avenue, New Haven, CT 06520, USA

2 Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520, USA

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

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

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

6 Department Statistics, University of California at Berkeley, 367 Evans Hall Berkeley, CA 94720, USA

7 Department of Computer Science, Stanford University, 353 Serra Mall, Stanford, CA 94305, USA

8 European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK

9 Department of Genetics, Stanford University School of Medicine, Mail Stop-5120, Stanford, CA 94305, USA

10 Department of Computer Science, Yale University, 51 Prospect Street, New Haven, CT 06511, USA

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Citation and License

Genome Biology 2012, 13:R48  doi:10.1186/gb-2012-13-9-r48

Published: 5 September 2012

Abstract

Background

Transcription factors function by binding different classes of regulatory elements. The Encyclopedia of DNA Elements (ENCODE) project has recently produced binding data for more than 100 transcription factors from about 500 ChIP-seq experiments in multiple cell types. While this large amount of data creates a valuable resource, it is nonetheless overwhelmingly complex and simultaneously incomplete since it covers only a small fraction of all human transcription factors.

Results

As part of the consortium effort in providing a concise abstraction of the data for facilitating various types of downstream analyses, we constructed statistical models that capture the genomic features of three paired types of regions by machine-learning methods: firstly, regions with active or inactive binding; secondly, those with extremely high or low degrees of co-binding, termed HOT and LOT regions; and finally, regulatory modules proximal or distal to genes. From the distal regulatory modules, we developed computational pipelines to identify potential enhancers, many of which were validated experimentally. We further associated the predicted enhancers with potential target transcripts and the transcription factors involved. For HOT regions, we found a significant fraction of transcription factor binding without clear sequence motifs and showed that this observation could be related to strong DNA accessibility of these regions.

Conclusions

Overall, the three pairs of regions exhibit intricate differences in chromosomal locations, chromatin features, factors that bind them, and cell-type specificity. Our machine learning approach enables us to identify features potentially general to all transcription factors, including those not included in the data.