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Abstract Cross‐species prediction of TF binding remains a major challenge due to the rapid evolutionary turnover of individual TF binding sites, resulting in cross‐species predictive performance being consistently worse than within‐species performance. In this study, a novel Nucleotide‐Level Deep Neural Network (NLDNN) is first proposed to predict TF binding within or across species. NLDNN regards the task of TF binding prediction as a nucleotide‐level regression task, which takes DNA sequences as input and directly predicts experimental coverage values. Beyond predictive performance, it also assesses model performance by locating potential TF binding regions, discriminating TF‐specific single‐nucleotide polymorphisms (SNPs), and identifying causal disease‐associated SNPs. The experimental results show that NLDNN outperforms the competing methods in these tasks. Then, a dual‐path framework is designed for adversarial training of NLDNN to further improve the cross‐species prediction performance by pulling the domain space of human and mouse species closer. Through comparison and analysis, it finds that adversarial training not only can improve the cross‐species prediction performance between humans and mice but also enhance the ability to locate TF binding regions and discriminate TF‐specific SNPs. By visualizing the predictions, it is figured out that the framework corrects some mispredictions by amplifying the coverage values of incorrectly predicted peaks.

Circular RNAs (circRNAs) play vital roles in transcription and translation. Identification of circRNA-RBP (RNA-binding protein) interaction sites has become a fundamental step in molecular and cell biology. Deep learning (DL)-based methods have been proposed to predict circRNA-RBP interaction sites and achieved impressive identification performance. However, those methods cannot effectively capture long-distance dependencies, and cannot effectively utilize the interaction information of multiple features. To overcome those limitations, we propose a DL-based model iCRBP-LKHA using deep hybrid networks for identifying circRNA-RBP interaction sites. iCRBP-LKHA adopts five encoding schemes. Meanwhile, the neural network architecture, which consists of large kernel convolutional neural network (LKCNN), convolutional block attention module with one-dimensional convolution (CBAM-1D) and bidirectional gating recurrent unit (BiGRU), can explore local information, global context information and multiple features interaction information automatically. To verify the effectiveness of iCRBP-LKHA, we compared its performance with shallow learning algorithms on 37 circRNAs datasets and 37 circRNAs stringent datasets. And we compared its performance with state-of-the-art DL-based methods on 37 circRNAs datasets, 37 circRNAs stringent datasets and 31 linear RNAs datasets. The experimental results not only show that iCRBP-LKHA outperforms other competing methods, but also demonstrate the potential of this model in identifying other RNA-RBP interaction sites.

Abstract Background The rapid emergence of single-cell RNA-seq (scRNA-seq) data presents remarkable opportunities for broad investigations through integration analyses. However, most integration models are black boxes that lack interpretability or are hard to train. Results To address the above issues, we propose scInterpreter, a deep learning-based interpretable model. scInterpreter substantially outperforms other state-of-the-art (SOTA) models in multiple benchmark datasets. In addition, scInterpreter is extensible and can integrate and annotate atlas scRNA-seq data. We evaluated the robustness of scInterpreter in a variety of situations. Through comparison experiments, we found that with a knowledge prior, the training process can be significantly accelerated. Finally, we conducted interpretability analysis for each dimension (pathway) of cell representation in the embedding space. Conclusions The results showed that the cell representations obtained by scInterpreter are full of biological significance. Through weight sorting, we found several new genes related to pathways in PBMC dataset. In general, scInterpreter is an effective and interpretable integration tool. It is expected that scInterpreter will bring great convenience to the study of single-cell transcriptomics.

Introduction: CircRNA-protein binding plays a critical role in complex biological activity and disease. Various deep learning-based algorithms have been proposed to identify CircRNA-protein binding sites. These methods predict whether the CircRNA sequence includes protein binding sites from the sequence level, and primarily concentrate on analysing the sequence specificity of CircRNA-protein binding. For model performance, these methods are unsatisfactory in accurately predicting motif sites that have special functions in gene expression.Methods: In this study, based on the deep learning models that implement pixel-level binary classification prediction in computer vision, we viewed the CircRNA-protein binding sites prediction as a nucleotide-level binary classification task, and use a fully convolutional neural networks to identify CircRNA-protein binding motif sites (CPBFCN).Results: CPBFCN provides a new path to predict CircRNA motifs. Based on the MEME tool, the existing CircRNA-related and protein-related database, we analysed the motif functions discovered by CPBFCN. We also investigated the correlation between CircRNA sponge and motif distribution. Furthermore, by comparing the motif distribution with different input sequence lengths, we found that some motifs in the flanking sequences of CircRNA-protein binding region may contribute to CircRNA-protein binding.Conclusion: This study contributes to identify circRNA-protein binding and provides help in understanding the role of circRNA-protein binding in gene expression regulation.

Accumulating evidence suggests that circRNAs play crucial roles in human diseases. CircRNA-disease association prediction is extremely helpful in understanding pathogenesis, diagnosis, and prevention, as well as identifying relevant biomarkers. During the past few years, a large number of deep learning (DL) based methods have been proposed for predicting circRNA-disease association and achieved impressive prediction performance. However, there are two main drawbacks to these methods. The first is these methods underutilize biometric information in the data. Second, the features extracted by these methods are not outstanding to represent association characteristics between circRNAs and diseases. In this study, we developed a novel deep learning model, named iCircDA-NEAE, to predict circRNA-disease associations. In particular, we use disease semantic similarity, Gaussian interaction profile kernel, circRNA expression profile similarity, and Jaccard similarity simultaneously for the first time, and extract hidden features based on accelerated attribute network embedding (AANE) and dynamic convolutional autoencoder (DCAE). Experimental results on the circR2Disease dataset show that iCircDA-NEAE outperforms other competing methods significantly. Besides, 16 of the top 20 circRNA-disease pairs with the highest prediction scores were validated by relevant literature. Furthermore, we observe that iCircDA-NEAE can effectively predict new potential circRNA-disease associations.

Abstract Background Circular RNAs (CircRNAs) play critical roles in gene expression regulation and disease development. Understanding the regulation mechanism of CircRNAs formation can help reveal the role of CircRNAs in various biological processes mentioned above. Back-splicing is important for CircRNAs formation. Back-splicing sites prediction helps uncover the mysteries of CircRNAs formation. Several methods were proposed for back-splicing sites prediction or circRNA-realted prediction tasks. Model performance was constrained by poor feature learning and using ability. Results In this study, CircCNN was proposed to predict pre-mRNA back-splicing sites. Convolution neural network and batch normalization are the main parts of CircCNN. Experimental results on three datasets show that CircCNN outperforms other baseline models. Moreover, PPM (Position Probability Matrix) features extract by CircCNN were converted as motifs. Further analysis reveals that some of motifs found by CircCNN match known motifs involved in gene expression regulation, the distribution of motif and special short sequence is important for pre-mRNA back-splicing. Conclusions In general, the findings in this study provide a new direction for exploring CircRNA-related gene expression regulatory mechanism and identifying potential targets for complex malignant diseases. The datasets and source code of this study are freely available at: https://github.com/szhh521/CircCNN .

In recent years, major advances have been made in various chromosome conformation capture technologies to further satisfy the needs of researchers for high-quality, high-resolution contact interactions. Discriminating the loops from genome-wide contact interactions is crucial for dissecting three-dimensional(3D) genome structure and function. Here, we present a deep learning method to predict genome-wide chromatin loops, called DLoopCaller, by combining accessible chromatin landscapes and raw Hi-C contact maps. Some available orthogonal data ChIA-PET/HiChIP and Capture Hi-C were used to generate positive samples with a wider contact matrix which provides the possibility to find more potential genome-wide chromatin loops. The experimental results demonstrate that DLoopCaller effectively improves the accuracy of predicting genome-wide chromatin loops compared to the state-of-the-art method Peakachu. Moreover, compared to two of most popular loop callers, such as HiCCUPS and Fit-Hi-C, DLoopCaller identifies some unique interactions. We conclude that a combination of chromatin landscapes on the one-dimensional genome contributes to understanding the 3D genome organization, and the identified chromatin loops reveal cell-type specificity and transcription factor motif co-enrichment across different cell lines and species.

The study of transcriptional regulation is still difficult yet fundamental in molecular biology research. Recent research has shown that the double helix structure of nucleotides plays an important role in improving the accuracy and interpretability of transcription factor binding sites (TFBSs). Although several computational methods have been designed to take both DNA sequence and DNA shape features into consideration simultaneously, how to design an efficient model is still an intractable topic. In this paper, we proposed a hybrid convolutional recurrent neural network (CNN/RNN) architecture, CRPTS, to predict TFBSs by combining DNA sequence and DNA shape features. The novelty of our proposed method relies on three critical aspects: (1) the application of a shared hybrid CNN and RNN has the ability to efficiently extract features from large-scale genomic sequences obtained by high-throughput technology; (2) the common patterns were found from DNA sequences and their corresponding DNA shape features; (3) our proposed CRPTS can capture local structural information of DNA sequences without completely relying on DNA shape data. A series of comprehensive experiments on 66 in vitro datasets derived from universal protein binding microarrays (uPBMs) shows that our proposed method CRPTS obviously outperforms the state-of-the-art methods.

Transcription factors (TFs) play an important role in regulating gene expression, thus the identification of the sites bound by them has become a fundamental step for molecular and cellular biology. In this paper, we developed a deep learning framework leveraging existing fully convolutional neural networks (FCN) to predict TF-DNA binding signals at the base-resolution level (named as FCNsignal). The proposed FCNsignal can simultaneously achieve the following tasks: (i) modeling the base-resolution signals of binding regions; (ii) discriminating binding or non-binding regions; (iii) locating TF-DNA binding regions; (iv) predicting binding motifs. Besides, FCNsignal can also be used to predict opening regions across the whole genome. The experimental results on 53 TF ChIP-seq datasets and 6 chromatin accessibility ATAC-seq datasets show that our proposed framework outperforms some existing state-of-the-art methods. In addition, we explored to use the trained FCNsignal to locate all potential TF-DNA binding regions on a whole chromosome and predict DNA sequences of arbitrary length, and the results show that our framework can find most of the known binding regions and accept sequences of arbitrary length. Furthermore, we demonstrated the potential ability of our framework in discovering causal disease-associated single-nucleotide polymorphisms (SNPs) through a series of experiments.