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Abstract High-resolution reconstruction of spatial chromosome organizations from chromatin contact maps is highly demanded, but is hindered by extensive pairwise constraints, substantial missing data, and limited resolution and cell-type availabilities. Here, we present FLAMINGO, a computational method that addresses these challenges by compressing inter-dependent Hi-C interactions to delineate the underlying low-rank structures in 3D space, based on the low-rank matrix completion technique. FLAMINGO successfully generates 5 kb- and 1 kb-resolution spatial conformations for all chromosomes in the human genome across multiple cell-types, the largest resources to date. Compared to other methods using various experimental metrics, FLAMINGO consistently demonstrates superior accuracy in recapitulating observed structures with raises in scalability by orders of magnitude. The reconstructed 3D structures efficiently facilitate discoveries of higher-order multi-way interactions, imply biological interpretations of long-range QTLs, reveal geometrical properties of chromatin, and provide high-resolution references to understand structural variabilities. Importantly, FLAMINGO achieves robust predictions against high rates of missing data and significantly boosts 3D structure resolutions. Moreover, FLAMINGO shows vigorous cross cell-type structure predictions that capture cell-type specific spatial configurations via integration of 1D epigenomic signals. FLAMINGO can be widely applied to large-scale chromatin contact maps and expand high-resolution spatial genome conformations for diverse cell-types.
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Principal curve approaches for inferring 3D chromatin architecture
Summary Three-dimensional (3D) genome spatial organization is critical for numerous cellular processes, including transcription, while certain conformation-driven structural alterations are frequently oncogenic. Genome architecture had been notoriously difficult to elucidate, but the advent of the suite of chromatin conformation capture assays, notably Hi-C, has transformed understanding of chromatin structure and provided downstream biological insights. Although many findings have flowed from direct analysis of the pairwise proximity data produced by these assays, there is added value in generating corresponding 3D reconstructions deriving from superposing genomic features on the reconstruction. Accordingly, many methods for inferring 3D architecture from proximity data have been advanced. However, none of these approaches exploit the fact that single chromosome solutions constitute a one-dimensional (1D) curve in 3D. Rather, this aspect has either been addressed by imposition of constraints, which is both computationally burdensome and cell type specific, or ignored with contiguity imposed after the fact. Here, we target finding a 1D curve by extending principal curve methodology to the metric scaling problem. We illustrate how this approach yields a sequence of candidate solutions, indexed by an underlying smoothness or degrees-of-freedom parameter, and propose methods for selection from this sequence. We apply the methodology to Hi-C data obtained on IMR90 cells and so are positioned to evaluate reconstruction accuracy by referencing orthogonal imaging data. The results indicate the utility and reproducibility of our principal curve approach in the face of underlying structural variation.
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- Award ID(s):
- 2013736
- PAR ID:
- 10226370
- Date Published:
- Journal Name:
- Biostatistics
- ISSN:
- 1465-4644
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract MotivationHigh-throughput conformation capture experiments, such as Hi-C provide genome-wide maps of chromatin interactions, enabling life scientists to investigate the role of the three-dimensional structure of genomes in gene regulation and other essential cellular functions. A fundamental problem in the analysis of Hi-C data is how to compare two contact maps derived from Hi-C experiments. Detecting similarities and differences between contact maps are critical in evaluating the reproducibility of replicate experiments and for identifying differential genomic regions with biological significance. Due to the complexity of chromatin conformations and the presence of technology-driven and sequence-specific biases, the comparative analysis of Hi-C data is analytically and computationally challenging. ResultsWe present a novel method called Selfish for the comparative analysis of Hi-C data that takes advantage of the structural self-similarity in contact maps. We define a novel self-similarity measure to design algorithms for (i) measuring reproducibility for Hi-C replicate experiments and (ii) finding differential chromatin interactions between two contact maps. Extensive experimental results on simulated and real data show that Selfish is more accurate and robust than state-of-the-art methods. Availability and implementationhttps://github.com/ucrbioinfo/Selfishmore » « less
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Abstract The organization of chromatin into self-interacting domains is universal among eukaryotic genomes, though how and why they form varies considerably. Here we report a chromosome-scale reference genome assembly of pepper ( Capsicum annuum ) and explore its 3D organization through integrating high-resolution Hi-C maps with epigenomic, transcriptomic, and genetic variation data. Chromatin folding domains in pepper are as prominent as TADs in mammals but exhibit unique characteristics. They tend to coincide with heterochromatic regions enriched with retrotransposons and are frequently embedded in loops, which may correlate with transcription factories. Their boundaries are hotspots for chromosome rearrangements but are otherwise depleted for genetic variation. While chromatin conformation broadly affects transcription variance, it does not predict differential gene expression between tissues. Our results suggest that pepper genome organization is explained by a model of heterochromatin-driven folding promoted by transcription factories and that such spatial architecture is under structural and functional constraints.more » « less
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Abstract In the last decade, DNA-DNA proximity ligation assays opened powerful new ways to study the 3D organization of genomes and have become a mainstay experimental technology. Yet many aspects of these experiments remain poorly understood. We study the inner workings of DNA-DNA proximity ligation assays through numerical experiments and theoretical modeling. Chromosomes are modeled at nucleosome resolution and evolved in time via molecular dynamics. A virtual Hi-C experiment reproduces, in-silico, the different steps of the Hi-C protocol, including: crosslinking of chromatin to an underlying proteic matrix, enzymatic digestion of DNA, and subsequent proximity ligation of DNA open ends. The protocol is simulated on ensembles of different structures as well as individual structures, enabling the construction of ligation maps and the calculation of ligation probabilities as functions of genomic and Euclidean distance. The methods help to assess the effect of the many variables of the Hi-C experiment and of subsequent data processing methods on the quality of the final results.more » « less
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null (Ed.)Abstract The recently developed Hi-C technique has been widely applied to map genome-wide chromatin interactions. However, current methods for analyzing diploid Hi-C data cannot fully distinguish between homologous chromosomes. Consequently, the existing diploid Hi-C analyses are based on sparse and inaccurate allele-specific contact matrices, which might lead to incorrect modeling of diploid genome architecture. Here we present ASHIC, a hierarchical Bayesian framework to model allele-specific chromatin organizations in diploid genomes. We developed two models under the Bayesian framework: the Poisson-multinomial (ASHIC-PM) model and the zero-inflated Poisson-multinomial (ASHIC-ZIPM) model. The proposed ASHIC methods impute allele-specific contact maps from diploid Hi-C data and simultaneously infer allelic 3D structures. Through simulation studies, we demonstrated that ASHIC methods outperformed existing approaches, especially under low coverage and low SNP density conditions. Additionally, in the analyses of diploid Hi-C datasets in mouse and human, our ASHIC-ZIPM method produced fine-resolution diploid chromatin maps and 3D structures and provided insights into the allelic chromatin organizations and functions. To summarize, our work provides a statistically rigorous framework for investigating fine-scale allele-specific chromatin conformations. The ASHIC software is publicly available at https://github.com/wmalab/ASHIC.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1093/biostatistics/kxaa046
