Enhancers play a critical role in gene expression regulation. However, their accurate prediction remains a significant challenge due to the limited feature information provided by sequence semantics. To address this issue, we propose a novel multimodal framework, termed iEnhancer-Fusion, for enhancer identification and classification. The proposed model integrates two complementary modalities: DNA sequence features extracted using DNABERT-2, and DNA breathing features captured through a hybrid network comprising convolutional layer and Multi-Head Attention mechanism. These heterogeneous features are further fused via a Cross-Attention mechanism, enabling deep interaction between modalities and effectively overcoming the representational limitations of sequence-only models. Comparative experiments against seven representative enhancer prediction methods across two tasks demonstrate that iEnhancer-Fusion achieves superior performance across all key evaluation metrics. Specifically, in Task 1, the model achieves average ACC, MCC, and AUC scores of$82.70 \%, 65.52 \%$, and 87.35 %, respectively; in Task 2, the average scores for ACC, MCC, and AUC are$93.10 \%, 86.88 \%$, and 97.54 %, respectively.

MOTIVATION: Transcription factors are pivotal in the regulation of gene expression, and accurate identification of transcription factor binding sites (TFBSs) at high resolution is crucial for understanding the mechanisms underlying gene regulation. The task of identifying TFBSs from DNA sequences is a significant challenge in the field of computational biology today. To address this challenge, a variety of computational approaches have been developed. However, these methods face limitations in their ability to achieve high-resolution identification and often lack interpretability. RESULTS: We propose BertSNR, an interpretable deep learning framework for identifying TFBSs at single-nucleotide resolution. BertSNR integrates sequence-level and token-level information by multi-task learning based on pre-trained DNA language models. Benchmarking comparisons show that our BertSNR outperforms the existing state-of-the-art methods in TFBS predictions. Importantly, we enhanced the interpretability of the model through attentional weight visualization and motif analysis, and discovered the subtle relationship between attention weight and motif. Moreover, BertSNR effectively identifies TFBSs in promoter regions, facilitating the study of intricate gene regulation. AVAILABILITY AND IMPLEMENTATION: The BertSNR source code can be found at https://github.com/lhy0322/BertSNR.

Drug-drug interaction (DDI) can trigger many adverse effects in patients and has emerged as a threat to medicine and public health. Therefore, it is important to predict potential drug interactions since it can provide combination strategies of drugs for systematic and effective treatment. Existing deep learning-based methods often rely on DDI functional networks, or use them as an important part of the model information source. However, it is difficult to discover the interactions of a new drug. To address the above limitations, we propose a geometric molecular graph representation learning model (Mol-DDI) for DDI prediction based on the basic assumption that structure determines function. Mol-DDI only considers the covalent and non-covalent bond information of molecules, then it uses the pre-training idea of large-scale models to learn drug molecular representations and predict drug interactions during the fine-tuning process. Experimental results show that the Mol-DDI model outperforms others on the three datasets and performs better in predicting new drug interaction experiments.

Inferring potential drug indications plays a vital role in the drug discovery process. It can be time-consuming and costly to discover novel drug indications through biological experiments. Recently, graph learning-based methods have gained popularity for this task. These methods typically treat the prediction task as a binary classification problem, focusing on modeling associations between drugs and diseases within a graph. However, labeled data for drug indication prediction is often limited and expensive to acquire. Contrastive learning addresses this challenge by aligning similar drug-disease pairs and separating dissimilar pairs in the embedding space. Thus, we developed a model called DrIGCL for drug indication prediction, which utilizes graph convolutional networks and contrastive learning. DrIGCL incorporates drug structure, disease comorbidities, and known drug indications to extract representations of drugs and diseases. By combining contrastive and classification losses, DrIGCL predicts drug indications effectively. In multiple runs of hold-out validation experiments, DrIGCL consistently outperformed existing computational methods for drug indication prediction, particularly in terms of top-k. Furthermore, our ablation study has demonstrated a significant improvement in the predictive capabilities of our model when utilizing contrastive learning. Finally, we validated the practical usefulness of DrIGCL by examining the predicted novel indications of Aspirin.

MOTIVATION: Protein kinases have been the focus of drug discovery research for many years because they play a causal role in many human diseases. Understanding the binding profile of kinase inhibitors is a prerequisite for drug discovery, and traditional methods of predicting kinase inhibitors are time-consuming and inefficient. Calculation-based predictive methods provide a relatively low-cost and high-efficiency approach to the rapid development and effective understanding of the binding profile of kinase inhibitors. Particularly, the continuous improvement of network pharmacology methods provides unprecedented opportunities for drug discovery, network-based computational methods could be employed to aggregate the effective information from heterogeneous sources, which have become a new way for predicting the binding profile of kinase inhibitors. RESULTS: In this study, we proposed a network-based influence deep diffusion model, named IDDkin, for enhancing the prediction of kinase inhibitors. IDDkin uses deep graph convolutional networks, graph attention networks and adaptive weighting methods to diffuse the effective information of heterogeneous networks. The updated kinase and compound representations are used to predict potential compound-kinase pairs. The experimental results show that the performance of IDDkin is superior to the comparison methods, including the state-of-the-art kinase inhibitor prediction method and the classic model widely used in relationship prediction. In experiments conducted to verify its generalizability and in case studies, the IDDkin model also shows excellent performance. All of these results demonstrate the powerful predictive ability of the IDDkin model in the field of kinase inhibitors. AVAILABILITY AND IMPLEMENTATION: Source code and data can be downloaded from https://github.com/CS-BIO/IDDkin. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Combinatorial drug therapy is a promising way for treating cancers, which can reduce drug side effects and improve drug efficacy. However, due to the large-scale combinatorial space, it is difficult to quickly and effectively identify novel synergistic drug combinations for further implementing combinatorial drug therapy. The computational method of fusing multi-source knowledge is a time- and cost-efficient strategy to infer synergistic drug combinations for testing. However, for the existing computational methods of inferring synergistic drug combinations, it still remains a challenging to effectively combine multi-source information to achieve the desired results. Hence, in this study, we developed a novel Inference method of Synergistic Drug Combinations based on Symmetric Meta-Path (ISDCSMP), which can systematically and accurately prioritize synergistic drug combinations in a novel drug-target heterogeneous network integrating multi-source information. In the experiment, ISDCSMP outperformed the state-of-the-art methods in terms of AUC and precision on the benchmark dataset in five-fold cross validation. Moreover, we further illustrated performances of different ways for obtaining the combination coefficients, and analyzed the influences of the maximum meta-path length. The performances of various single meta-paths were described in five-fold cross validation. Finally, we confirmed the practical usefulness of ISDCSMP with the predicted novel synergistic drug combinations. The source code of ISDCSMP is available at https://github.com/KDDing/ISDCSMP.

Small molecule(SM) drugs can affect the expression of miRNAs, which plays crucial roles in many important biological processes. The chemical structure and clinical information of small molecule can simultaneously incorporate information such as anatomical distribution, therapeutic effects and structural characteristics. It is necessary to develop a novel model that incorporates small molecule chemical structure and clinical information to reveal the unknown small molecule-miRNA associations. In this study, we developed a new framework based on non-negative matrix factorization, called SMANMF, to discover the potential small molecules-miRNAs associations. First, the functional similarity of two miRNAs can be obtained by computing the overlap of the target gene sets in which the miRNAs interact together, and we integrated two types of small molecule similarities, including chemical similarity and clinical similarity. Then, we utilized a non-negative matrix factorization model to discover the unknown relationship between small molecules and miRNAs. The evaluation results indicate that our model can achieve superior prediction performance compared with previous approaches in 5-fold cross-validation. At the same time, the results of case studies also reveal that the SMANMF model has good predictive performance for predicting the potential association between small molecules and miRNAs.

The molecular components with the functional interdependencies in human cell form complicated biological network. Diseases are mostly caused by the perturbations of the composite of the interaction multi-biomolecules, rather than an abnormality of a single biomolecule. Furthermore, new biological functions and processes could be revealed by discovering novel biological entity relationships. Hence, more and more biologists focus on studying the complex biological system instead of the individual biological components. The emergence of heterogeneous information network (HIN) offers a promising way to systematically explore complicated and heterogeneous relationships between various molecules for apparently distinct phenotypes. In this review, we first present the basic definition of HIN and the biological system considered as a complex HIN. Then, we discuss the topological properties of HIN and how these can be applied to detect network motif and functional module. Afterwards, methodologies of discovering relationships between disease and biomolecule are presented. Useful insights on how HIN aids in drug development and explores human interactome are provided. Finally, we analyze the challenges and opportunities for uncovering combinatorial patterns among pharmacogenomics and cell-type detection based on single-cell genomic data.

Long non-coding RNAs (lncRNAs) have been shown to be involved in multiple biological processes and play critical roles in tumorigenesis. Numerous lncRNAs have been discovered in diverse species, but the functions of most lncRNAs still remain unclear. Meanwhile, their expression patterns and regulation mechanisms are also far from being fully understood. With the advances of high-throughput technologies, the increasing availability of genomic data creates opportunities for deciphering the molecular mechanism and underlying pathogenesis of human diseases. Here, we develop an integrative framework called JONMF to identify lncRNA-mRNA co-expression modules based on the sample-matched lncRNA and mRNA expression profiles. We formulate the module detection task as an optimization problem with joint orthogonal non-negative matrix factorization that could effectively prevent multicollinearity and produce a good modularity interpretation. The constructed lncRNA-mRNA co-expression network and the gene-gene interaction network are used as the network-regularized constraints to improve the module accuracy, while the sparsity constraints are simultaneously utilized to achieve modular sparse solutions. We applied JONMF to human ovarian cancer dataset and the experiment results demonstrate that the proposed method can effectively discover biologically functional co-expression modules, which may provide insights into the function of lncRNAs and molecular mechanism of human diseases.

Combinatorial therapy may reduce drug side effects and improve drug efficacy, making combination therapy a promising strategy to treat complex diseases. However, in the existing computational methods, the natural properties and network knowledge of drugs have not been adequately and simultaneously considered, making it difficult to identify effective drug combinations. Computational methods that incorporate multiple sources of information (biological, chemical, pharmacological, and network knowledge) offer more opportunities to screen synergistic drug combinations. Therefore, we developed a novel Ensemble Prediction framework of Synergistic Drug Combinations (EPSDC) to accurately and efficiently predict drug combinations by integrating information from multiple-sources. EPSDC constructs feature vector of drug pair by concatenating different types of drug similarities, and then uses these groups in a feature-based base predictor. Next, transductive learning is applied on heterogeneous drug-target networks to achieve a network-based score for the drug pair. Finally, two types of ensemble rules are introduced to combine the feature-based score and the network-based score, and then potential drug combinations are prioritized. To demonstrate the effect of the ensemble rule, comprehensive experiments were conducted to compare single models and ensemble models. The experimental results indicated that our method outperformed the state-of-the-art method in five-fold cross validation and de novo prediction tests on the two benchmark datasets. We further analyzed the effect of maximum length of the meta-path and the impacts of different types of features. Moreover, the practical usefulness of our method was confirmed in the predicted novel drug combinations. The source code of EPSDC is available at https://github.com/KDDing/EPSDC.

Predicting the miRNA-target interactions (MTIs) is a critical task for elucidating mechanistic roles of miRNAs in pathophysiology. However, most existing techniques have a higher false positive because the precise miRNA target mechanisms are poorly known. Considering that ensemble methods can take advantage of the complementary knowledge in different methods, we propose an alternative optimization framework, Inferring MiRNA Targets based on Restricted Boltzmann Machines (IMTRBM), to enhance the accuracy of previous prediction results. First, the proposed method directly constructs a weighted MTI network though the results predicted by individual methods and each miRNA target pair is weighted based on the frequency appearing in these results. Second, we transform the miRNA-target prediction problem into a complete bipartite graph model, named restricted Boltzmann machine, and utilize a practical learning procedure to train our model and make predictions. Our results show that the algorithm outperforms individual miRNA-target prediction approach in the number of validated miRNA targets at cutoffs of top list. Moreover, our framework can tolerate the decrease and increase of predicted MTIs and even discover new miRNA targets, which have been a challenge to predict for any individual methods. Finally, for the miRNAs that are not appearing in IMTRBM, we design a new method to supplement IMTRBM based on the intuition that similar miRNAs have similar functions, which also achieves a comparable result. The source code of IMTRBM is available at https://github.com/liuying201705/IMTRBM.

MOTIVATION: MicroRNAs (miRNAs) play crucial roles in post-transcriptional regulations and various cellular processes. The identification of disease-related miRNAs provides great insights into the underlying pathogenesis of diseases at a system level. However, most existing computational approaches are biased towards known miRNA-disease associations, which is inappropriate for those new diseases or miRNAs without any known association information. RESULTS: In this study, we propose a new method with graph regularized non-negative matrix factorization in heterogeneous omics data, called GRNMF, to discover potential associations between miRNAs and diseases, especially for new diseases and miRNAs or those diseases and miRNAs with sparse known associations. First, we integrate the disease semantic information and miRNA functional information to estimate disease similarity and miRNA similarity, respectively. Considering that there is no available interaction observed for new diseases or miRNAs, a preprocessing step is developed to construct the interaction score profiles that will assist in prediction. Next, a graph regularized non-negative matrix factorization framework is utilized to simultaneously identify potential associations for all diseases. The results indicated that our proposed method can effectively prioritize disease-associated miRNAs with higher accuracy compared with other recent approaches. Moreover, case studies also demonstrated the effectiveness of GRNMF to infer unknown miRNA-disease associations for those novel diseases and miRNAs. AVAILABILITY AND IMPLEMENTATION: The code of GRNMF is freely available at https://github.com/XIAO-HN/GRNMF/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The discovery of human disease-related miRNA is a challenging problem for complex disease biology research. For existing computational methods, it is difficult to achieve excellent performance with sparse known miRNA-disease association verified by biological experiment. Here, we develop CPTL, a Collective Prediction based on Transduction Learning, to systematically prioritize miRNAs related to disease. By combining disease similarity, miRNA similarity with known miRNA-disease association, we construct a miRNA-disease network for predicting miRNA-disease association. Then, CPTL calculates relevance score and updates the network structure iteratively, until a convergence criterion is reached. The relevance score of node including miRNA and disease is calculated by the use of transduction learning based on its neighbors. The network structure is updated using relevance score, which increases the weight of important links. To show the effectiveness of our method, we compared CPTL with existing methods based on HMDD datasets. Experimental results indicate that CPTL outperforms existing approaches in terms of AUC, precision, recall, and F1-score. Moreover, experiments performed with different number of iterations verify that CPTL has good convergence. Besides, it is analyzed that the varying of weighted parameters affect predicted results. Case study on breast cancer has further confirmed the identification ability of CPTL.