Dataset Information

SuperTAD: robust detection of hierarchical topologically associated domains with optimized structural information.

ABSTRACT: Topologically associating domains (TADs) are the organizational units of chromosome structures. TADs can contain TADs, thus forming a hierarchy. TAD hierarchies can be inferred from Hi-C data through coding trees. However, the current method for computing coding trees is not optimal. In this paper, we propose optimal algorithms for this computation. In comparison with seven state-of-art methods using two public datasets, from GM12878 and IMR90 cells, SuperTAD shows a significant enrichment of structural proteins around detected boundaries and histone modifications within TADs and displays a high consistency between various resolutions of identical Hi-C matrices.

SUBMITTER: Zhang YW

PROVIDER: S-EPMC7831269 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

SuperTAD: robust detection of hierarchical topologically associated domains with optimized structural information.

Zhang Yu Wei YW Wang Meng Bo MB Li Shuai Cheng SC

Genome biology 20210125 1

Topologically associating domains (TADs) are the organizational units of chromosome structures. TADs can contain TADs, thus forming a hierarchy. TAD hierarchies can be inferred from Hi-C data through coding trees. However, the current method for computing coding trees is not optimal. In this paper, we propose optimal algorithms for this computation. In comparison with seven state-of-art methods using two public datasets, from GM12878 and IMR90 cells, SuperTAD shows a significant enrichment of st ...[more]

PMID: 33494803

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Project description:Experiments based on chromosome conformation capture have shown that mammalian genomes are partitioned into topologically associating domains (TADs), within which the chromatin fiber preferentially interacts. TADs may provide three-dimensional scaffolds allowing genes to contact their appropriate distal regulatory DNA sequences (e.g., enhancers) and thus to be properly regulated. Understanding the cell-to-cell and temporal variability of the chromatin fiber within TADs, and what determines them, is thus of great importance to better understand transcriptional regulation. We recently described an equilibrium polymer model that can accurately predict cell-to-cell variation of chromosome conformation within single TADs, from chromosome conformation capture-based data. Here we further analyze the conformational and energetic properties of our model. We show that the chromatin fiber within TADs can easily fluctuate between several conformational states, which are hierarchically organized and are not separated by important free energy barriers, and that this is facilitated by the fact that the chromatin fiber within TADs is close to the onset of the coil-globule transition. We further show that in this dynamic state the properties of the chromatin fiber, and its contact probabilities in particular, are determined in a nontrivial manner not only by site-specific interactions between strongly interacting loci along the fiber, but also by nonlocal correlations between pairs of contacts. Finally, we use live-cell experiments to measure the dynamics of the chromatin fiber in mouse embryonic stem cells, in combination with dynamical simulations, and predict that conformational changes within one TAD are likely to occur on timescales that are much shorter than the duration of one cell cycle. This suggests that genes and their regulatory elements may come together and disassociate several times during a cell cycle. These results have important implications for transcriptional regulation as they support the concept of highly dynamic interactions driven by a complex interplay between site-specific interactions and the intrinsic biophysical properties of the chromatin fiber.

Project description:BACKGROUND:Topologically 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. RESULTS:In 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. CONCLUSIONS:The 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/.

Dataset Information

SuperTAD: robust detection of hierarchical topologically associated domains with optimized structural information.

Publications

SuperTAD: robust detection of hierarchical topologically associated domains with optimized structural information.

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