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1. Hierarchical Reconstruction of High-Resolution 3D Models of Large Chromosomes

   https://doi.org/10.1038/s41598-019-41369-w  

   Trieu, Tuan ; Oluwadare, Oluwatosin ; Cheng, Jianlin ( March 2019 , Scientific Reports)

   Eukaryotic chromosomes are often composed of components organized into multiple scales, such as nucleosomes, chromatin fibers, topologically associated domains (TAD), chromosome compartments, and chromosome territories. Therefore, reconstructing detailed 3D models of chromosomes in high resolution is useful for advancing genome research. However, the task of constructing quality high-resolution 3D models is still challenging with existing methods. Hence, we designed a hierarchical algorithm, called Hierarchical3DGenome, to reconstruct 3D chromosome models at high resolution (<=5 Kilobase (KB)). The algorithm first reconstructs high-resolution 3D models at TAD level. The TAD models are then assembled to form complete high-resolution chromosomal models. The assembly of TAD models is guided by a complete low-resolution chromosome model. The algorithm is successfully used to reconstruct 3D chromosome models at 5 KB resolution for the human B-cell (GM12878). These high-resolution models satisfy Hi-C chromosomal contacts well and are consistent with models built at lower (i.e. 1 MB) resolution, and with the data of fluorescentin situhybridization experiments. The Java source code of Hierarchical3DGenome and its user manual are available herehttps://github.com/BDM-Lab/Hierarchical3DGenome.

    

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2. Differential roles of positive and negative supercoiling in organizing the E. coli genome

   https://doi.org/10.1093/nar/gkad1139  

   Fu, Ziqi ; Guo, Monica S. ; Zhou, Weiqiang ; Xiao, Jie ( December 2023 , Nucleic Acids Research)

   This study aims to explore whether and how positive and negative supercoiling contribute to the three-dimensional (3D) organization of the bacterial genome. We used recently published Escherichia coli GapR ChIP-seq and TopoI ChIP-seq (also called EcTopoI-seq) data, which marks positive and negative supercoiling sites, respectively, to study how supercoiling correlates with the spatial contact maps obtained from chromosome conformation capture sequencing (Hi-C and 5C). We find that supercoiled chromosomal loci have overall higher Hi-C contact frequencies than sites that are not supercoiled. Surprisingly, positive supercoiling corresponds to higher spatial contact than negative supercoiling. Additionally, positive, but not negative, supercoiling could be identified from Hi-C data with high accuracy. We further find that the majority of positive and negative supercoils coincide with highly active transcription units, with a minor group likely associated with replication and other genomic processes. Our results show that both positive and negative supercoiling enhance spatial contact, with positive supercoiling playing a larger role in bringing genomic loci closer in space. Based on our results, we propose new physical models of how the E. coli chromosome is organized by positive and negative supercoils.

    

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3. HiCube: interactive visualization of multiscale and multimodal Hi-C and 3D genome data

   https://doi.org/10.1093/bioinformatics/btad154  

   Ye, Tiantian ; Hu, Yangyang ; Pun, Sydney ; Ma, Wenxiu ; Alkan, ed., Can ( March 2023 , Bioinformatics)

   HiCube is a lightweight web application for interactive visualization and exploration of diverse types of genomics data at multiscale resolutions. Especially, HiCube displays synchronized views of Hi-C contact maps and 3D genome structures with user-friendly annotation and configuration tools, thereby facilitating the study of 3D genome organization and function.

   HiCube is implemented in Javascript and can be installed via NPM. The source code is freely available at GitHub (https://github.com/wmalab/HiCube).

    

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4. Deep learning-based subdivision approach for large scale macromolecules structure recovery from electron cryo tomograms

   https://doi.org/10.1093/bioinformatics/btx230  

   Xu, Min ; Chai, Xiaoqi ; Muthakana, Hariank ; Liang, Xiaodan ; Yang, Ge ; Zeev-Ben-Mordehai, Tzviya ; Xing, Eric P. ( July 2017 , Bioinformatics)

   Cellular Electron CryoTomography (CECT) enables 3D visualization of cellular organization at near-native state and in sub-molecular resolution, making it a powerful tool for analyzing structures of macromolecular complexes and their spatial organizations inside single cells. However, high degree of structural complexity together with practical imaging limitations makes the systematic de novo discovery of structures within cells challenging. It would likely require averaging and classifying millions of subtomograms potentially containing hundreds of highly heterogeneous structural classes. Although it is no longer difficult to acquire CECT data containing such amount of subtomograms due to advances in data acquisition automation, existing computational approaches have very limited scalability or discrimination ability, making them incapable of processing such amount of data.

   To complement existing approaches, in this article we propose a new approach for subdividing subtomograms into smaller but relatively homogeneous subsets. The structures in these subsets can then be separately recovered using existing computation intensive methods. Our approach is based on supervised structural feature extraction using deep learning, in combination with unsupervised clustering and reference-free classification. Our experiments show that, compared with existing unsupervised rotation invariant feature and pose-normalization based approaches, our new approach achieves significant improvements in both discrimination ability and scalability. More importantly, our new approach is able to discover new structural classes and recover structures that do not exist in training data.

   Source code freely available at http://www.cs.cmu.edu/∼mxu1/software.

   Supplementary data are available at Bioinformatics online.

    

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5. Interphase chromosomes of the Aedes aegypti mosquito are liquid crystalline and can sense mechanical cues

   https://doi.org/10.1038/s41467-023-35909-2  

   Contessoto, Vinícius G. ; Dudchenko, Olga ; Aiden, Erez Lieberman ; Wolynes, Peter G. ; Onuchic, José N. ; Di Pierro, Michele ( December 2023 , Nature Communications)

   Abstract We use data-driven physical simulations to study the three-dimensional architecture of the Aedes aegypti genome. Hi-C maps exhibit both a broad diagonal and compartmentalization with telomeres and centromeres clustering together. Physical modeling reveals that these observations correspond to an ensemble of 3D chromosomal structures that are folded over and partially condensed. Clustering of the centromeres and telomeres near the nuclear lamina appears to be a necessary condition for the formation of the observed structures. Further analysis of the mechanical properties of the genome reveals that the chromosomes of Aedes aegypti , by virtue of their atypical structural organization, are highly sensitive to the deformation of the nuclei. This last finding provides a possible physical mechanism linking mechanical cues to gene regulation. 

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