Advances in computational identification and modeling of DNA regulatory elements in the human genome

Dongwon Lee, Michael A. Beer

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Identification of DNA regulatory elements in the human genome remains a significant challenge. Variation in these regulatory elements can contribute to disease in many ways by altering protein levels. Enhancers constitute an important class of these DNA regulatory elements, and a major component of current research is focused on a more complete understanding of enhancer function and improved techniques for enhancer detection. We recently developed a computational approach to identify enhancers from primary DNA sequence using a support vector machine (kmer-SVM) framework. Here we show that the kmer-SVM model can accurately predict tissue specific enhancer activity without any prior knowledge about TF binding sites. We adapt this approach to predict genomic TF binding data generated by the ENCODE project, showing that genomic MYC binding can be accurately predicted from local DNA sequence with the kmer-SVM. We find similar accuracy with an SVM using PWMs representing known TF binding specificities. By integrating Chip-seq and expression data, we show that while much of MYC binding is shared between ENCODE cell types and is promoter proximal, cell-type specific MYC binding is distal and is correlated with enhanced cell-specific expression of nearby (~50kb) genes. The distinction between shared and cell-specific MYC binding is determined by DNA sequence variation around the canonical MYC binding site, which by itself cannot distinguish cell-specific binding events. These results suggest that tissue specific enhancer activity is specified by primary DNA sequence, that local sequence context controls tissue specific activity through cooperative TF interactions, and that local context sequence features can be identified from genomic binding data.

Original languageEnglish (US)
Title of host publication4th International Conference on Biomedical Engineering in Vietnam
Pages328-331
Number of pages4
DOIs
StatePublished - Jan 1 2013
Event4th International Conference on the Development of Biomedical Engineering in Vietnam - Ho Chi Minh City, Viet Nam
Duration: Jan 8 2012Jan 10 2012

Publication series

NameIFMBE Proceedings
Volume40 IFMBE
ISSN (Print)1680-0737

Other

Other4th International Conference on the Development of Biomedical Engineering in Vietnam
Country/TerritoryViet Nam
CityHo Chi Minh City
Period1/8/121/10/12

Keywords

  • computational biology
  • enhancers
  • genomics
  • transcriptional regulation

ASJC Scopus subject areas

  • Bioengineering
  • Biomedical Engineering

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