cudaMMC: GPU-enhanced multiscale Monte Carlo chromatin 3D modelling.

MOTIVATION: Investigating the 3D structure of chromatin provides new insights into transcriptional regulation. With the evolution of 3C next-generation sequencing methods like ChiA-PET and Hi-C, the surge in data volume has highlighted the need for more efficient chromatin spatial modelling algorithms. This study introduces the cudaMMC method, based on the Simulated Annealing Monte Carlo approach and enhanced by GPU-accelerated computing, to efficiently generate ensembles of chromatin 3D structures. RESULTS: The cudaMMC calculations demonstrate significantly faster performance with better stability compared to our previous method on the same workstation. cudaMMC also substantially reduces the computation time required for generating ensembles of large chromatin models, making it an invaluable tool for studying chromatin spatial conformation. AVAILABILITY AND IMPLEMENTATION: Open-source software and manual and sample data are freely available on https://github.com/SFGLab/cudaMMC.

3D-GNOME 3.0: a three-dimensional genome modelling engine for analysing changes of promoter-enhancer contacts in the human genome.

In the current update, we added a feature for analysing changes in spatial distances between promoters and enhancers in chromatin 3D model ensembles. We updated our datasets by the novel in situ CTCF and RNAPII ChIA-PET chromatin loops obtained from the GM12878 cell line mapped to the GRCh38 genome assembly and extended the 1000 Genomes SVs dataset. To handle the new datasets, we applied GPU acceleration for the modelling engine, which gives a speed-up of 30× versus the previous versions. To improve visualisation and data analysis, we embedded the IGV tool for viewing ChIA-PET arcs with additional genes and SVs annotations. For 3D model visualisation, we added a new viewer: NGL, where we provided colouring by gene and enhancer location. The models are downloadable in mmcif and xyz format. The web server is hosted and performs calculations on DGX A100 GPU servers that provide optimal performance with multitasking. 3D-GNOME 3.0 web server provides unique insights into the topological mechanism of human variations at the population scale with high speed-up and is freely available at https://3dgnome.mini.pw.edu.pl/.

Identification of miRNA Biomarkers for Diverse Cancer Types Using Statistical Learning Methods at the Whole-Genome Scale.

Genome-wide analysis of miRNA molecules can reveal important information for understanding the biology of cancer. Typically, miRNAs are used as features in statistical learning methods in order to train learning models to predict cancer. This motivates us to propose a method that integrates clustering and classification techniques for diverse cancer types with survival analysis via regression to identify miRNAs that can potentially play a crucial role in the prediction of different types of tumors. Our method has two parts. The first part is a feature selection procedure, called the stochastic covariance evolutionary strategy with forward selection (SCES-FS), which is developed by integrating stochastic neighbor embedding (SNE), the covariance matrix adaptation evolutionary strategy (CMA-ES), and classifiers, with the primary objective of selecting biomarkers. SNE is used to reorder the features by performing an implicit clustering with highly correlated neighboring features. A subset of features is selected heuristically to perform multi-class classification for diverse cancer types. In the second part of our method, the most important features identified in the first part are used to perform survival analysis via Cox regression, primarily to examine the effectiveness of the selected features. For this purpose, we have analyzed next generation sequencing data from The Cancer Genome Atlas in form of miRNA expression of 1,707 samples of 10 different cancer types and 333 normal samples. The SCES-FS method is compared with well-known feature selection methods and it is found to perform better in multi-class classification for the 17 selected miRNAs, achieving an accuracy of 96%. Moreover, the biological significance of the selected miRNAs is demonstrated with the help of network analysis, expression analysis using hierarchical clustering, KEGG pathway analysis, GO enrichment analysis, and protein-protein interaction analysis. Overall, the results indicate that the 17 selected miRNAs are associated with many key cancer regulators, such as MYC, VEGFA, AKT1, CDKN1A, RHOA, and PTEN, through their targets. Therefore the selected miRNAs can be regarded as putative biomarkers for 10 types of cancer.

3D-GNOME 2.0: a three-dimensional genome modeling engine for predicting structural variation-driven alterations of chromatin spatial structure in the human genome.

Structural variants (SVs) that alter DNA sequence emerge as a driving force involved in the reorganisation of DNA spatial folding, thus affecting gene transcription. In this work, we describe an improved version of our integrated web service for structural modeling of three-dimensional genome (3D-GNOME), which now incorporates all types of SVs to model changes to the reference 3D conformation of chromatin. In 3D-GNOME 2.0, the default reference 3D genome structure is generated using ChIA-PET data from the GM12878 cell line and SVs data are sourced from the population-scale catalogue of SVs identified by the 1000 Genomes Consortium. However, users may also submit their own structural data to set a customized reference genome structure, and/or a custom input list of SVs. 3D-GNOME 2.0 provides novel tools to inspect, visualize and compare 3D models for regions that differ in terms of their linear genomic sequence. Contact diagrams are displayed to compare the reference 3D structure with the one altered by SVs. In our opinion, 3D-GNOME 2.0 is a unique online tool for modeling and analyzing conformational changes to the human genome induced by SVs across populations. It can be freely accessed at https://3dgnome.cent.uw.edu.pl/.

Correction to: Spatial chromatin architecture alteration by structural variations in human genomes at the population scale.

Following publication of the original article [1], it was noticed that the incorrect Fig. 2 and Fig. 3. were processed during production. It was also noticed that Fig. 4a was processed with a superfluous "1e7" symbol in the upper right corner.

Spatial chromatin architecture alteration by structural variations in human genomes at the population scale.

BACKGROUND: The number of reported examples of chromatin architecture alterations involved in the regulation of gene transcription and in disease is increasing. However, no genome-wide testing has been performed to assess the abundance of these events and their importance relative to other factors affecting genome regulation. This is particularly interesting given that a vast majority of genetic variations identified in association studies are located outside coding sequences. This study attempts to address this lack by analyzing the impact on chromatin spatial organization of genetic variants identified in individuals from 26 human populations and in genome-wide association studies. RESULTS: We assess the tendency of structural variants to accumulate in spatially interacting genomic segments and design an algorithm to model chromatin conformational changes caused by structural variations. We show that differential gene transcription is closely linked to the variation in chromatin interaction networks mediated by RNA polymerase II. We also demonstrate that CTCF-mediated interactions are well conserved across populations, but enriched with disease-associated SNPs. Moreover, we find boundaries of topological domains as relatively frequent targets of duplications, which suggest that these duplications can be an important evolutionary mechanism of genome spatial organization. CONCLUSIONS: This study assesses the critical impact of genetic variants on the higher-order organization of chromatin folding and provides insight into the mechanisms regulating gene transcription at the population scale, of which local arrangement of chromatin loops seems to be the most significant. It provides the first insight into the variability of the human 3D genome at the population scale.

Taking promoters out of enhancers in sequence based predictions of tissue-specific mammalian enhancers.

BACKGROUND: Many genetic diseases are caused by mutations in non-coding regions of the genome. These mutations are frequently found in enhancer sequences, causing disruption to the regulatory program of the cell. Enhancers are short regulatory sequences in the non-coding part of the genome that are essential for the proper regulation of transcription. While the experimental methods for identification of such sequences are improving every year, our understanding of the rules behind the enhancer activity has not progressed much in the last decade. This is especially true in case of tissue-specific enhancers, where there are clear problems in predicting specificity of enhancer activity. RESULTS: We show a random-forest based machine learning approach capable of matching the performance of the current state-of-the-art methods for enhancer prediction. Then we show that it is, similarly to other published methods, frequently cross-predicting enhancers as active in different tissues, making it less useful for predicting tissue specific activity. Then we proceed to show that the problem is related to the fact that the enhancer predicting models exhibit a bias towards predicting gene promoters as active enhancers. Then we show that using a two-step classifier can lead to lower cross-prediction between tissues. CONCLUSIONS: We provide whole-genome predictions of human heart and brain enhancers obtained with two-step classifier.