Abstract
BackgroundTopologically associating domains (TADs) are genomic regions with varying lengths. The interactions within TADs are more frequent than those between different TADs. TADs or sub-TADs are considered the structural and functional units of the mammalian genomes. Although TADs are important for understanding how genomes function, we have limited knowledge about their 3D structural properties.ResultsIn this study, we designed and benchmarked three metrics for capturing the three-dimensional and two-dimensional structural signatures of TADs, which can help better understand TADs’ structural properties and the relationships between structural properties and genetic and epigenetic features. The first metric for capturing 3D structural properties is radius of gyration, which in this study is used to measure the spatial compactness of TADs. The mass value of each DNA bead in a 3D structure is novelly defined as one or more genetic or epigenetic feature(s). The second metric is folding degree. The last metric is exponent parameter, which is used to capture the 2D structural properties based on TADs’ Hi-C contact matrices. In general, we observed significant correlations between the three metrics and the genetic and epigenetic features. We made the same observations when using H3K4me3, transcription start sites, and RNA polymerase II to represent the mass value in the modified radius-of-gyration metric. Moreover, we have found that the TADs in the clusters of depleted chromatin states apparently correspond to smaller exponent parameters and larger radius of gyrations. In addition, a new objective function of multidimensional scaling for modelling chromatin or TADs 3D structures was designed and benchmarked, which can handle the DNA bead-pairs with zero Hi-C contact values.ConclusionsThe web server for reconstructing chromatin 3D structures using multiple different objective functions and the related source code are publicly available at http://dna.cs.miami.edu/3DChrom/.
Highlights
Associating domains (TADs) are genomic regions with varying lengths
While the above-mentioned studies are based on population-cell Hi-C data, it is important to notice the emergence of single-cell Hi-C technique revealing cellto-cell variabilities and related method that can reconstruct chromosomal Three dimensional (3D) structures based on single-cell Hi-C data [13, 14]
We removed multiple experimental artifacts defined in [19]: first, the PCR duplicates, resulting in multiple paired-end reads mapped to the same genomic location were removed using Picard; second, we discarded the reads with mapping quality less than or equal to 10; and third, paired-end reads were discarded if the two ends were mapped to the same fragment or the sum of the distances between the mapping site of each end of a paired-end read and its corresponding nearest restriction cut site was larger than a certain threshold (500 bp suggested in [6])
Summary
Associating domains (TADs) are genomic regions with varying lengths. The interactions within TADs are more frequent than those between different TADs. TADs are important for understanding how genomes function, we have limited knowledge about their 3D structural properties. Varoquaux et al [11] and Ay et al [9] designed new objective functions of metric MDS to model the 3D structures of chromatins based on experimental and simulated Hi-C data. Zhang et al developed ChromSDE [12] that infers 3D structures of chromosomes by semi-definite programming and uses golden section search to find the best parameter for converting Hi-C contacts into spatial target distances. While the above-mentioned studies are based on population-cell Hi-C data, it is important to notice the emergence of single-cell Hi-C technique revealing cellto-cell variabilities and related method that can reconstruct chromosomal 3D structures based on single-cell Hi-C data [13, 14]
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