Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency
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ABSTRACT:
ORGANISM(S): Homo sapiens (human)
SUBMITTER: Yujie Sun
PROVIDER: S-BSST648 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:BackgroundMetazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Although various genetic and epigenetic signatures have been linked to the replication efficiency of origins, there is no consensus on how the selection of origins is determined.ResultsWe apply dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We find that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase. Intriguingly, while both high-efficiency and low-efficiency origins are distributed homogeneously in the TAD during the G1 phase, high-efficiency origins relocate to the TAD periphery before the S phase. Origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observe that the replication machinery protein PCNA forms immobile clusters around TADs at the G1/S transition, explaining why origins at the TAD periphery are preferentially fired.ConclusionOur work reveals a new origin selection mechanism that the replication efficiency of origins is determined by their physical distribution in the chromatin domain, which undergoes a transcription-dependent structural re-organization process. Our model explains the complex links between replication origin efficiency and many genetic and epigenetic signatures that mark active transcription. The coordination between DNA replication, transcription, and chromatin organization inside individual TADs also provides new insights into the biological functions of sub-domain chromatin structural dynamics.
| S-EPMC8276456 | biostudies-literature
Project description:Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.
| S-EPMC4251741 | biostudies-literature
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.
| S-EPMC4816701 | biostudies-literature
Project description: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/.
| S-EPMC6886161 | biostudies-literature
Project description:Recent chromosome conformation capture (3C) derived techniques have revealed that topologically associating domain (TAD) is a pervasive element in chromatin three-dimensional (3D) organization. However, there is currently no parameter to quantitatively measure the structural characteristics of TADs, thus obscuring our understanding on the structural and functional differences among TADs. Based on our finding that there exist intrinsic chromatin interaction patterns in TADs, we define a theoretical parameter, called aggregation preference (AP), to characterize TAD structures by capturing the interaction aggregation degree. Applying this defined parameter to 11 Hi-C data sets generated by both traditional and in situ Hi-C experimental pipelines, our analyses reveal that heterogeneous structures exist among TADs, and this structural heterogeneity is significantly correlated to DNA sequences, epigenomic signals and gene expressions. Although TADs can be stable in genomic positions across cell lines, structural comparisons show that a considerable number of stable TADs undergo significantly structural rearrangements during cell changes. Moreover, the structural change of TAD is tightly associated with its transcription remodeling. Altogether, the theoretical parameter defined in this work provides a quantitative method to link structural characteristics and biological functions of TADs, and this linkage implies that chromatin interaction pattern has the potential to mark transcription activity in TADs.
| S-EPMC4551926 | biostudies-literature
Project description:We investigate chromosome organization within the nucleus using polymer models whose formulation is closely guided by experiments in live yeast cells. We employ bead-spring chromosome models together with loop formation within the chains and the presence of nuclear bodies to quantify the extent to which these mechanisms shape the topological landscape in the interphase nucleus. By investigating the genome as a dynamical system, we show that domains of high chromosomal interactions can arise solely from the polymeric nature of the chromosome arms due to entropic interactions and nuclear confinement. In this view, the role of bio-chemical related processes is to modulate and extend the duration of the interacting domains.
| S-EPMC4937343 | biostudies-literature
Project description:Chromatin is a polymer complex of DNA and proteins that regulates gene expression. The three-dimensional (3D) structure and organization of chromatin controls DNA transcription and replication. High-throughput chromatin conformation capture techniques generate Hi-C maps that can provide insight into the 3D structure of chromatin. Hi-C maps can be represented as a symmetric matrix [Formula: see text], where each element represents the average contact probability or number of contacts between chromatin loci i and j. Previous studies have detected topologically associating domains (TADs), or self-interacting regions in [Formula: see text] within which the contact probability is greater than that outside the region. Many algorithms have been developed to identify TADs within Hi-C maps. However, most TAD identification algorithms are unable to identify nested or overlapping TADs and for a given Hi-C map there is significant variation in the location and number of TADs identified by different methods. We develop a novel method to identify TADs, KerTAD, using a kernel-based technique from computer vision and image processing that is able to accurately identify nested and overlapping TADs. We benchmark this method against state-of-the-art TAD identification methods on both synthetic and experimental data sets. We find that the new method consistently has higher true positive rates (TPR) and lower false discovery rates (FDR) than all tested methods for both synthetic and manually annotated experimental Hi-C maps. The TPR for KerTAD is also largely insensitive to increasing noise and sparsity, in contrast to the other methods. We also find that KerTAD is consistent in the number and size of TADs identified across replicate experimental Hi-C maps for several organisms. Thus, KerTAD will improve automated TAD identification and enable researchers to better correlate changes in TADs to biological phenomena, such as enhancer-promoter interactions and disease states.
| S-EPMC11249266 | biostudies-literature
Project description:A current question in the high-order organization of chromatin is whether topologically associating domains (TADs) are distinct from other hierarchical chromatin domains. However, due to the unclear TAD definition in tradition, the structural and functional uniqueness of TAD is not well studied. In this work, we refined TAD definition by further constraining TADs to the optimal separation on global intra-chromosomal interactions. Inspired by this constraint, we developed a novel method, called HiTAD, to detect hierarchical TADs from Hi-C chromatin interactions. HiTAD performs well in domain sensitivity, replicate reproducibility and inter cell-type conservation. With a novel domain-based alignment proposed by us, we defined several types of hierarchical TAD changes which were not systematically studied previously, and subsequently used them to reveal that TADs and sub-TADs differed statistically in correlating chromosomal compartment, replication timing and gene transcription. Finally, our work also has the implication that the refinement of TAD definition could be achieved by only utilizing chromatin interactions, at least in part. HiTAD is freely available online.
| S-EPMC5737579 | biostudies-literature
Project description:BackgroundRecent increasing evidence indicates that three-dimensional chromosome structure plays an important role in genomic function. Topologically associating domains (TADs) are self-interacting regions that have been shown to be a chromosomal structural unit. During evolution, these are conserved based on checking synteny block cross species. Are there common TAD patterns across species or cell lines?ResultsTo address the above question, we propose a novel task-TAD recognition-as opposed to traditional TAD identification. Specifically, we treat Hi-C maps as images, thus re-casting TAD recognition as image pattern recognition, for which we use a convolutional neural network and a residual neural network. In addition, we propose an elegant way to generate non-TAD data for binary classification. We demonstrate deep learning performance which is quite promising, AUC > 0.80, through cross-species and cell-type validation.ConclusionsTADs have been shown to be conserved during evolution. Interestingly, our results confirm that the TAD recognition model is practical across species, which indicates that TADs between human and mouse show common patterns from an image classification point of view. Our approach could be a new way to identify TAD variations or patterns among Hi-C maps. For example, TADs of two Hi-C maps are conserved if the two classification models are exchangeable.
| S-EPMC9732975 | biostudies-literature
Project description:Topologically associating domains (TADs) are critical structural units in three-dimensional genome organization of mammalian genome. Dynamic reorganizations of TADs between health and disease states are associated with essential genome functions. However, computational methods for identifying reorganized TADs are still in the early stages of development. Here, we present DiffDomain, an algorithm leveraging high-dimensional random matrix theory to identify structurally reorganized TADs using high-throughput chromosome conformation capture (Hi-C) contact maps. Method comparison using multiple real Hi-C datasets reveals that DiffDomain outperforms alternative methods for false positive rates, true positive rates, and identifying a new subtype of reorganized TADs. Applying DiffDomain to Hi-C data from different cell types and disease states demonstrates its biological relevance. Identified reorganized TADs are associated with structural variations and epigenomic changes such as changes in CTCF binding sites. By applying to a single-cell Hi-C data from mouse neuronal development, DiffDomain can identify reorganized TADs between cell types with reasonable reproducibility using pseudo-bulk Hi-C data from as few as 100 cells per condition. Moreover, DiffDomain reveals differential cell-to-population variability and heterogeneous cell-to-cell variability in TADs. Therefore, DiffDomain is a statistically sound method for better comparative analysis of TADs using both Hi-C and single-cell Hi-C data.
| S-EPMC10787792 | biostudies-literature