A computational method to predict topologically associating domain boundaries combining histone Marks and sequence information

Abstract

Background: The three-dimensional (3D) structure of chromatins plays significant roles during cell differentiation and development. Hi-C and other 3C-based technologies allow us to look deep into the chromatin architectures. Many studies have suggested that topologically associating domains (TAD), as the structure and functional unit, are conserved across different organs. However, our understanding about the underlying mechanism of the TAD boundary formation is still limited. Results: We developed a computational method, TAD-Lactuca, to infer this structure by taking the contextual information of the epigenetic modification signals and the primary DNA sequence information on the genome. TAD-Lactuca is found stable in the case of multi-resolutions and different datasets. It could achieve high accuracy and even outperforms the state-of-art methods when the sequence patterns were incorporated. Moreover, several transcript factor binding motifs, besides the well-known CCCTC-binding factor (CTCF) motif, were found significantly enriched on the boundaries. Conclusions: We provided a low cost, effective method to predict TAD boundaries. Above results suggested the incorporation of sequence features could significantly improve the performance. The sequence motif enrichment analysis indicates several gene regulation motifs around the boundaries, which is consistent with TADs may serve as the functional units of gene regulation and implies the sequence patterns would be important in chromatin folding.