The emergence of single-cell RNA sequencing (scRNA-seq) technology has transformed our understanding of cellular diversity, yet it presents notable challenges for cell type annotation due to data's high dimensionality and sparsity. To tackle these issues, we present scSorterDL, an innovative approach that combines penalized Linear Discriminant Analysis (pLDA), swarm learning, and deep neural networks (DNNs) to improve cell type classification. In scSorterDL, we generate numerous random subsets of the data and apply pLDA models to each subset to capture varied data aspects. The model outputs are then consolidated using a DNN that identifies complex relationships among the pLDA scores, enhancing classification accuracy by considering interactions that simpler methods might overlook. Utilizing GPU computing for both swarm learning and deep learning, scSorterDL adeptly manages large datasets and high-dimensional gene expression data. We tested scSorterDL on 13 real scRNA-seq datasets from diverse species, tissues, and platforms, as well as on 20 pairs of cross-platform datasets. Our method surpassed nine current cell annotation tools in both accuracy and robustness, indicating exceptional performance in both cross-validation and cross-platform contexts. These findings underscore the potential of scSorterDL as an effective and adaptable tool for automated cell type annotation in scRNA-seq research. The code is available on GitHub: https://github.com/kellen8hao/scSorterDL.

Skeletal muscle regeneration is a complex process orchestrated by diverse cell populations within a dynamic niche. In response to muscle damage and intercellular signaling, these cells undergo cell fate and migration decisions including quiescence, activation, proliferation, differentiation, infiltration, apoptosis, and exfiltration. The emergence of single-cell RNA sequencing (scRNA-seq) studies of muscle regeneration offers a significant opportunity to refine models of regeneration and enhance our understanding of cellular interactions. To better understand how crosstalk between cell types governs cell fate decisions and cell population dynamics, we developed a novel non-linear ordinary differential equation model guided by scRNA-seq data. Our model consists of 9 variables and 17 parameters, capturing the dynamics of key myogenic lineage and immune cell types. We calibrated time-series scRNA-seq data to units of cells per cubic millimeter of tissue and fit our model's parameters to capture the observed dynamics, validating on an independent time series. The model successfully captures key features of regeneration dynamics, particularly after incorporating a novel regulatory interaction between M2 macrophages and satellite cells that has been hypothesized in the literature. Our model lays a foundation for future computational explorations of muscle regeneration, modeling of disease conditions, and in silico testing of therapeutic strategies.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for millions of deaths around the world. To help contribute to the understanding of crucial knowledge and to further generate new hypotheses relevant to SARS-CoV-2 and human protein interactions, we make use of the information abundant Biomine probabilistic database and extend the experimentally identified SARS-CoV-2-human protein-protein interaction (PPI) network in silico. We generate an extended network by integrating information from the Biomine database, the PPI network and other experimentally validated results. To generate novel hypotheses, we focus on the high-connectivity sub-communities that overlap most with the integrated experimentally validated results in the extended network. Therefore, we propose a new data analysis pipeline that can efficiently compute core decomposition on the extended network and identify dense subgraphs. We then evaluate the identified dense subgraph and the generated hypotheses in three contexts: literature validation for uncovered virus targeting genes and proteins, gene function enrichment analysis on subgraphs and literature support on drug repurposing for identified tissues and diseases related to COVID-19. The major types of the generated hypotheses are proteins with their encoding genes and we rank them by sorting their connections to the integrated experimentally validated nodes. In addition, we compile a comprehensive list of novel genes, and proteins potentially related to COVID-19, as well as novel diseases which might be comorbidities. Together with the generated hypotheses, our results provide novel knowledge relevant to COVID-19 for further validation.

Motivation: Many peak detection algorithms have been proposed for ChIP-seq data analysis, but it is not obvious which algorithm and what parameters are optimal for any given dataset. In contrast, regions with and without obvious peaks can be easily labeled by visual inspection of aligned read counts in a genome browser. We propose a supervised machine learning approach for ChIP-seq data analysis, using labels that encode qualitative judgments about which genomic regions contain or do not contain peaks. The main idea is to manually label a small subset of the genome, and then learn a model that makes consistent peak predictions on the rest of the genome. Results: We created 7 new histone mark datasets with 12 826 visually determined labels, and analyzed 3 existing transcription factor datasets. We observed that default peak detection parameters yield high false positive rates, which can be reduced by learning parameters using a relatively small training set of labeled data from the same experiment type. We also observed that labels from different people are highly consistent. Overall, these data indicate that our supervised labeling method is useful for quantitatively training and testing peak detection algorithms. Availability and Implementation: Labeled histone mark data http://cbio.ensmp.fr/~thocking/chip-seq-chunk-db/ , R package to compute the label error of predicted peaks https://github.com/tdhock/PeakError. Contacts: [email protected] or [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

SUMMARY: DMEAS is the first user-friendly tool dedicated to analyze the distribution of DNA methylation patterns for the quantification of epigenetic heterogeneity. It supports the analysis of both locus-specific and genome-wide bisulfite sequencing data. DMEAS progressively scans the mapping results of bisulfite sequencing reads to extract DNA methylation patterns for contiguous CpG dinucleotides. It determines the DNA methylation level and calculates methylation entropy for genomic segments to enable the quantitative assessment of DNA methylation variations observed in cell populations. AVAILABILITY AND IMPLEMENTATION: DMEAS program, user guide and all the testing data are freely available from http://sourceforge.net/projects/dmeas/files/

MOTIVATION: Chromatin regulators (CR) and transcription factors (TF) are important trans-acting factors regulating transcription process, and many efforts have been devoted to understand their underlying mechanisms in gene regulation. However, the influences of CR and TF regulation effects on nucleosomes during transcription are still minimally understood, and it remains to be determined the extent to which CR and TF regulatory effect shape the organization of nucleosomes in the genome. In this article we attempted to address this problem and examine the patterns of CR and TF regulation effects from the nucleosome perspective. RESULTS: Our results show that the CR and TF regulatory effects exhibit different paradigms of transcriptional control in Saccharomyces cerevisiae. We grouped yeast genes into two categories, 'CR-sensitive' genes and 'TF-sensitive' genes, based on how their expression profiles change upon deletion of CRs or TFs. We found that genes in these two groups have very different patterns of nucleosome organization. The promoters of CR-sensitive genes tend to have higher nucleosome occupancy, whereas the promoters of TF-sensitive genes are depleted of nucleosomes. Furthermore, the nucleosome profiles of CR-sensitive genes tend to show more dynamic characteristics than TF-sensitive genes. These results reveal that the nucleosome organizations of yeast genes have a strong impact on their mode of regulation, and there are differential regulation effects on nucleosomes between CRs and TFs. AVAILABILITY: http://www.utoronto.ca/zhanglab/papers/bioinfo_2010/.

MOTIVATION: Predicting protein interactions involving peptide recognition domains is essential for understanding the many important biological processes they mediate. It is important to consider the binding strength of these interactions to help us construct more biologically relevant protein interaction networks that consider cellular context and competition between potential binders. RESULTS: We developed a novel regression framework that considers both positive (quantitative) and negative (qualitative) interaction data available for mouse PDZ domains to quantitatively predict interactions between PDZ domains, a large peptide recognition domain family, and their peptide ligands using primary sequence information. First, we show that it is possible to learn from existing quantitative and negative interaction data to infer the relative binding strength of interactions involving previously unseen PDZ domains and/or peptides given their primary sequence. Performance was measured using cross-validated hold out testing and testing with previously unseen PDZ domain-peptide interactions. Second, we find that incorporating negative data improves quantitative interaction prediction. Third, we show that sequence similarity is an important prediction performance determinant, which suggests that experimentally collecting additional quantitative interaction data for underrepresented PDZ domain subfamilies will improve prediction. AVAILABILITY AND IMPLEMENTATION: The Matlab code for our SemiSVR predictor and all data used here are available at http://baderlab.org/Data/PDZAffinity.