Abstract
Chromatin conformation plays an important role in a variety of genomic processes, including genome replication, gene expression, and gene methylation. Hi-C data is frequently used to analyze structural features of chromatin, such as AB compartments, topologically associated domains, and 3D structural models. Recently, the genomics community has displayed growing interest in chromatin dynamics. Here, we present 4DMax, a novel method, which uses time-series Hi-C data to predict dynamic chromosome conformation. Using both synthetic data and real time-series Hi-C data from processes, such as induced pluripotent stem cell reprogramming and cardiomyocyte differentiation, we construct smooth four-dimensional models of individual chromosomes. These predicted 4D models effectively interpolate chromatin position across time, permitting prediction of unknown Hi-C contact maps at intermittent time points. Furthermore, 4DMax correctly recovers higher order features of chromatin, such as AB compartments and topologically associated domains, even at time points where Hi-C data is not made available to the algorithm. Contact map predictions made using 4DMax outperform naïve numerical interpolation in 87.7% of predictions on the induced pluripotent stem cell dataset. A/B compartment profiles derived from 4DMax interpolation showed higher similarity to ground truth than at least one profile generated from a neighboring time point in 100% of induced pluripotent stem cell experiments. Use of 4DMax may alleviate the cost of expensive Hi-C experiments by interpolating intermediary time points while also providing valuable visualization of dynamic chromatin changes.
Highlights
The three-dimensional (3D) conformation of the genome has been shown to play an important role in a variety of genomic processes, such as gene expression [1] genome replication [2] and gene methylation [3]
Bulk Hi-C has the major advantage of high read coverage; it has been empirically demonstrated that bulk Hi-C samples can have large amounts of structural variation, meaning different cells in the population are positioned in varying orientations
By using spatial restraints derived from Hi-C contact matrices, we provide a tool that permits the generation of a predictive 4D video of chromatin conformational changes throughout the time series. 4DMax can be used to interpolate higher order chromatin features, such as the AB compartment and topological associated domains (TADs), at times where no data is available while providing valuable visualizations of chromosomal processes
Summary
The three-dimensional (3D) conformation of the genome has been shown to play an important role in a variety of genomic processes, such as gene expression [1] genome replication [2] and gene methylation [3]. Hi-C experiments can be categorized as bulk [15] or single cell [16]. Bulk Hi-C experiments examine populations of cells, providing average contact information across millions of nuclei. Bulk Hi-C has the major advantage of high read coverage; it has been empirically demonstrated that bulk Hi-C samples can have large amounts of structural variation, meaning different cells in the population are positioned in varying orientations. To address this structural variation, some 3DModeling algorithms predict an ensemble of structures from a single
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