Transcription Factor Binding Site-based Alignment of Conserved Non-coding Sequences

Abdollahyan, F. Smeraldi, B. Noyvert and G. Elgar, 15th European Conference on Computational Biology (ECCB), 2016

Abstract:

The identification and functional characterization of regulatory modules in the human genome is a challenging task. Regulatory modules act through the sequence-specific binding of transcription factors and previous studies have demonstrated that co-occurrence of transcription factor binding sites (TFBSs) in close proximity can be a good indicator of regulatory activity. In this study, we analysed the co-occurrence of TFBSs within a set of highly conserved non-coding elements (CNEs) that are associated with the regulation of early vertebrate development. From a computational point of view, analysis of the co-occurrence of TFBSs is complicated by the fact that TFBSs overlap. This rules out the use of classic alignment algorithms (that cannot handle alternative motifs in sequences) or k-mer-based approaches (that count the occurrences of motifs and would enumerate all alternative motifs indiscriminately). Our approach is fundamentally different in that we wrote each CNE as a sequence of symbols, each representing a TFBS identified within that element. We then constructed a graph representation of the CNEs which accounts for the ambiguity due to the overlapping of TFBSs and used a dynamic programming approach to find the optimal alignment between these graphs. We then computed the relative enrichment of short sequences of TFBSs in the alignments of CNEs compared to a background distribution. Our results identify a number of enriched TFBS alignments within CNEs, including a regulatory signature that has been functionally validated in this set of CNEs previously and is associated with hindbrain enhancer activity.

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