How computer science can help in understanding the 3D genome architecture.

Chromosome conformation capture techniques are producing a huge amount of data about the architecture of our genome. These data can provide us with a better understanding of the events that induce critical regulations of the cellular function from small changes in the three-dimensional genome architecture. Generating a unified view of spatial, temporal, genetic and epigenetic properties poses various challenges of data analysis, visualization, integration and mining, as well as of high performance computing and big data management. Here, we describe the critical issues of this new branch of bioinformatics, oriented at the comprehension of the three-dimensional genome architecture, which we call 'Nucleome Bioinformatics', looking beyond the currently available tools and methods, and highlight yet unaddressed challenges and the potential approaches that could be applied for tackling them. Our review provides a map for researchers interested in using computer science for studying 'Nucleome Bioinformatics', to achieve a better understanding of the biological processes that occur inside the nucleus.

Hierarchical block matrices as efficient representations of chromosome topologies and their application for 3C data integration.

MOTIVATION: Recent advancements in molecular methods have made it possible to capture physical contacts between multiple chromatin fragments. The resulting association matrices provide a noisy estimate for average spatial proximity that can be used to gain insights into the genome organization inside the nucleus. However, extracting topological information from these data is challenging and their integration across resolutions is still poorly addressed. Recent findings suggest that a hierarchical approach could be advantageous for addressing these challenges. RESULTS: We present an algorithmic framework, which is based on hierarchical block matrices (HBMs), for topological analysis and integration of chromosome conformation capture (3C) data. We first describe chromoHBM, an algorithm that compresses high-throughput 3C (HiT-3C) data into topological features that are efficiently summarized with an HBM representation. We suggest that instead of directly combining HiT-3C datasets across resolutions, which is a difficult task, we can integrate their HBM representations, and describe chromoHBM-3C, an algorithm which merges HBMs. Since three-dimensional (3D) reconstruction can also benefit from topological information, we further present chromoHBM-3D, an algorithm which exploits the HBM representation in order to gradually introduce topological constraints to the reconstruction process. We evaluate our approach in light of previous image microscopy findings and epigenetic data, and show that it can relate multiple spatial scales and provide a more complete view of the 3D genome architecture. AVAILABILITY AND IMPLEMENTATION: The presented algorithms are available from: https://github.com/yolish/hbm CONTACT: ys388@cam.ac.uk or pl219@cam.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

FisHiCal: an R package for iterative FISH-based calibration of Hi-C data.

UNLABELLED: The fluorescence in situ hybridization (FISH) method has been providing valuable information on physical distances between loci (via image analysis) for several decades. Recently, high-throughput data on nearby chemical contacts between and within chromosomes became available with the Hi-C method. Here, we present FisHiCal, an R package for an iterative FISH-based Hi-C calibration that exploits in full the information coming from these methods. We describe here our calibration model and present 3D inference methods that we have developed for increasing its usability, namely, 3D reconstruction through local stress minimization and detection of spatial inconsistencies. We next confirm our calibration across three human cell lines and explain how the output of our methods could inform our model, defining an iterative calibration pipeline, with applications for quality assessment and meta-analysis. AVAILABILITY AND IMPLEMENTATION: FisHiCal v1.1 is available from http://cran.r-project.org/.

CytoHiC: a cytoscape plugin for visual comparison of Hi-C networks.

SUMMARY: With the introduction of the Hi-C method new and fundamental properties of the nuclear architecture are emerging. The ability to interpret data generated by this method, which aims to capture the physical proximity between and within chromosomes, is crucial for uncovering the three dimensional structure of the nucleus. Providing researchers with tools for interactive visualization of Hi-C data can help in gaining new and important insights. Specifically, visual comparison can pinpoint changes in spatial organization between Hi-C datasets, originating from different cell lines or different species, or normalized by different methods. Here, we present CytoHiC, a Cytsocape plugin, which allow users to view and compare spatial maps of genomic landmarks, based on normalized Hi-C datasets. CytoHiC was developed to support intuitive visual comparison of Hi-C data and integration of additional genomic annotations. AVAILABILITY: The CytoHiC plugin, source code, user manual, example files and documentation are available at: http://apps.cytoscape.org/apps/cytohicplugin

Coarse-to-Fine Multi-Scene Pose Regression With Transformers.

Absolute camera pose regressors estimate the position and orientation of a camera given the captured image alone. Typically, a convolutional backbone with a multi-layer perceptron (MLP) head is trained using images and pose labels to embed a single reference scene at a time. Recently, this scheme was extended to learn multiple scenes by replacing the MLP head with a set of fully connected layers. In this work, we propose to learn multi-scene absolute camera pose regression with Transformers, where encoders are used to aggregate activation maps with self-attention and decoders transform latent features and scenes encoding into pose predictions. This allows our model to focus on general features that are informative for localization, while embedding multiple scenes in parallel. We extend our previous MS-Transformer approach Shavit et al. (2021) by introducing a mixed classification-regression architecture that improves the localization accuracy. Our method is evaluated on commonly benchmark indoor and outdoor datasets and has been shown to exceed both multi-scene and state-of-the-art single-scene absolute pose regressors.

An integrated suite of fast docking algorithms.

The CAPRI experiment (Critical Assessment of Predicted Interactions) simulates realistic and diverse docking challenges, each case having specific properties that may be exploited by docking algorithms. Motivated by the different CAPRI challenges, we developed and implemented a comprehensive suite of docking algorithms. These were incorporated into a dynamic docking protocol, consisting of four main stages: (1) Biological and bioinformatics research aiming to predict the binding site residues, to define distance constraints between interface atoms and to analyze the flexibility of molecules; (2) Rigid or flexible docking, performed by the PatchDock or FlexDock method, which utilizes the information gathered in the previous step. Symmetric complexes are predicted by the SymmDock method; (3) Flexible refinement and reranking of the rigid docking solution candidates, performed by FiberDock; and finally, (4) clustering and filtering the results based on energy funnels. We analyzed the performance of our docking protocol on a large benchmark and on recent CAPRI targets. The analysis has demonstrated the importance of biological information gathering prior to docking, which significantly increased the docking success rate, and of the refinement and rescoring stage that significantly improved the ranking of the rigid docking solutions. Our failures were mostly a result of mishandling backbone flexibility, inaccurate homology modeling, or incorrect biological assumptions. Most of the methods are available at http://bioinfo3d.cs.tau.ac.il/.

Automated Synthesis and Analysis of Switching Gene Regulatory Networks.

Studying the gene regulatory networks (GRNs) that govern how cells change into specific cell types with unique roles throughout development is an active area of experimental research. The fate specification process can be viewed as a biological program prescribing the system dynamics, governed by a network of genetic interactions. To investigate the possibility that GRNs are not fixed but rather change their topology, for example as cells progress through commitment, we introduce the concept of Switching Gene Regulatory Networks (SGRNs) to enable the modelling and analysis of network reconfiguration. We define the synthesis problem of constructing SGRNs that are guaranteed to satisfy a set of constraints representing experimental observations of cell behaviour. We propose a solution to this problem that employs methods based upon Satisfiability Modulo Theories (SMT) solvers, and evaluate the feasibility and scalability of our approach by considering a set of synthetic benchmarks exhibiting possible biological behaviour of cell development. We outline how our approach is applied to a more realistic biological system, by considering a simplified network involved in the processes of neuron maturation and fate specification in the mammalian cortex.

Combining a wavelet change point and the Bayes factor for analysing chromosomal interaction data.

Over the past few decades we have witnessed great efforts to understand the cellular function at the cytoplasm level. Nowadays there is a growing interest in understanding the relationship between function and structure at the nuclear, chromosomal and sub-chromosomal levels. Data on chromosomal interactions that are now becoming available in unprecedented resolution and scale open the way to address this challenge. Consequently, there is a growing need for new methods and tools that will transform these data into knowledge and insights. Here, we have developed all the steps required for the analysis of chromosomal interaction data (Hi-C data). The result is a methodology which combines a wavelet change point with the Bayes factor for useful correction, segmentation and comparison of Hi-C data. We further developed chromoR, an R package that implements the methods presented here. The chromoR package provides researchers with a means to analyse chromosomal interaction data using statistical bioinformatics, offering a new and comprehensive solution to this task.