Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsWe 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.
Highlights
The spatial organization of the chromatin plays a key role in cellular processes [1], such as gene regulation, DNA replication and VDJ recombination [2,3,4]
Signal patterns around the topologically associating domains (TAD) boundaries We firstly investigated the CCCTC-binding factor (CTCF) and histone mark signal patterns around TAD boundaries, including H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K9me3, H3K27ac, H3K27me3 and H3K36me3
The bin _ size = 40kb and bin _ number = 10 resulted in a region of 840kb. We use this as an example to compare the enrichment difference of CTCF and eight different histone mark signals around the TAD boundaries and non-boundaries (Fig. 1)
Summary
The spatial organization of the chromatin plays a key role in cellular processes [1], such as gene regulation, DNA replication and VDJ (variable, diversity and joining genes) recombination [2,3,4]. Hi–C, has been a significant breakthrough in understanding the genome-wide chromatin structure. The most important discovery of 3D (three-dimensional) genome studies are possibly the hierarchical structures: compartments A or B [5], topologically associated domains (TADs) [6, 7] and chromatin loops [8, 9], which shape the genome and contribute to the functioning of the genome [10]. TADs, generally composed of many loops, being invariant and conservative during differentiation across cell types and tissues [7, 12], even between different species [2, 7, 11]. The three-dimensional (3D) structure of chromatins plays significant roles during cell differentiation and development. Many studies have suggested that topologically associating domains (TAD), as the structure and functional unit, are conserved across different organs. Our understanding about the underlying mechanism of the TAD boundary formation is still limited
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