scCorrector: a robust method for integrating multi-study single-cell data.

The advent of single-cell sequencing technologies has revolutionized cell biology studies. However, integrative analyses of diverse single-cell data face serious challenges, including technological noise, sample heterogeneity, and different modalities and species. To address these problems, we propose scCorrector, a variational autoencoder-based model that can integrate single-cell data from different studies and map them into a common space. Specifically, we designed a Study Specific Adaptive Normalization for each study in decoder to implement these features. scCorrector substantially achieves competitive and robust performance compared with state-of-the-art methods and brings novel insights under various circumstances (e.g. various batches, multi-omics, cross-species, and development stages). In addition, the integration of single-cell data and spatial data makes it possible to transfer information between different studies, which greatly expand the narrow range of genes covered by MERFISH technology. In summary, scCorrector can efficiently integrate multi-study single-cell datasets, thereby providing broad opportunities to tackle challenges emerging from noisy resources.

scInterpreter: a knowledge-regularized generative model for interpretably integrating scRNA-seq data.

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.

Nucleotide-level prediction of CircRNA-protein binding based on fully convolutional neural network.

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.

MV-CVIB: a microbiome-based multi-view convolutional variational information bottleneck for predicting metastatic colorectal cancer.

Introduction: Imbalances in gut microbes have been implied in many human diseases, including colorectal cancer (CRC), inflammatory bowel disease, type 2 diabetes, obesity, autism, and Alzheimer's disease. Compared with other human diseases, CRC is a gastrointestinal malignancy with high mortality and a high probability of metastasis. However, current studies mainly focus on the prediction of colorectal cancer while neglecting the more serious malignancy of metastatic colorectal cancer (mCRC). In addition, high dimensionality and small samples lead to the complexity of gut microbial data, which increases the difficulty of traditional machine learning models. Methods: To address these challenges, we collected and processed 16S rRNA data and calculated abundance data from patients with non-metastatic colorectal cancer (non-mCRC) and mCRC. Different from the traditional health-disease classification strategy, we adopted a novel disease-disease classification strategy and proposed a microbiome-based multi-view convolutional variational information bottleneck (MV-CVIB). Results: The experimental results show that MV-CVIB can effectively predict mCRC. This model can achieve AUC values above 0.9 compared to other state-of-the-art models. Not only that, MV-CVIB also achieved satisfactory predictive performance on multiple published CRC gut microbiome datasets. Discussion: Finally, multiple gut microbiota analyses were used to elucidate communities and differences between mCRC and non-mCRC, and the metastatic properties of CRC were assessed by patient age and microbiota expression.

DeepTPpred: A Deep Learning Approach With Matrix Factorization for Predicting Therapeutic Peptides by Integrating Length Information.

The abuse of traditional antibiotics has led to increased resistance of bacteria and viruses. Efficient therapeutic peptide prediction is critical for peptide drug discovery. However, most of the existing methods only make effective predictions for one class of therapeutic peptides. It is worth noting that currently no predictive method considers sequence length information as a distinct feature of therapeutic peptides. In this article, a novel deep learning approach with matrix factorization for predicting therapeutic peptides (DeepTPpred) by integrating length information are proposed. The matrix factorization layer can learn the potential features of the encoded sequence through the mechanism of first compression and then restoration. And the length features of the sequence of therapeutic peptides are embedded with encoded amino acid sequences. To automatically learn therapeutic peptide predictions, these latent features are input into the neural networks with self-attention mechanism. On eight therapeutic peptide datasets, DeepTPpred achieved excellent prediction results. Based on these datasets, we first integrated eight datasets to obtain a full therapeutic peptide integration dataset. Then, we obtained two functional integration datasets based on the functional similarity of the peptides. Finally, we also conduct experiments on the latest versions of the ACP and CPP datasets. Overall, the experimental results show that our work is effective for the identification of therapeutic peptides.

Predicting the Sequence Specificities of DNA-Binding Proteins by DNA Fine-Tuned Language Model With Decaying Learning Rates.

DNA-binding proteins (DBPs) play vital roles in the regulation of biological systems. Although there are already many deep learning methods for predicting the sequence specificities of DBPs, they face two challenges as follows. Classic deep learning methods for DBPs prediction usually fail to capture the dependencies between genomic sequences since their commonly used one-hot codes are mutually orthogonal. Besides, these methods usually perform poorly when samples are inadequate. To address these two challenges, we developed a novel language model for mining DBPs using human genomic data and ChIP-seq datasets with decaying learning rates, named DNA Fine-tuned Language Model (DFLM). It can capture the dependencies between genome sequences based on the context of human genomic data and then fine-tune the features of DBPs tasks using different ChIP-seq datasets. First, we compared DFLM with the existing widely used methods on 69 datasets and we achieved excellent performance. Moreover, we conducted comparative experiments on complex DBPs and small datasets. The results show that DFLM still achieved a significant improvement. Finally, through visualization analysis of one-hot encoding and DFLM, we found that one-hot encoding completely cut off the dependencies of DNA sequences themselves, while DFLM using language models can well represent the dependency of DNA sequences. Source code are available at: https://github.com/Deep-Bioinfo/DFLM.

Computational prediction and characterization of cell-type-specific and shared binding sites.

MOTIVATION: Cell-type-specific gene expression is maintained in large part by transcription factors (TFs) selectively binding to distinct sets of sites in different cell types. Recent research works have provided evidence that such cell-type-specific binding is determined by TF's intrinsic sequence preferences, cooperative interactions with co-factors, cell-type-specific chromatin landscapes and 3D chromatin interactions. However, computational prediction and characterization of cell-type-specific and shared binding sites is rarely studied. RESULTS: In this article, we propose two computational approaches for predicting and characterizing cell-type-specific and shared binding sites by integrating multiple types of features, in which one is based on XGBoost and another is based on convolutional neural network (CNN). To validate the performance of our proposed approaches, ChIP-seq datasets of 10 binding factors were collected from the GM12878 (lymphoblastoid) and K562 (erythroleukemic) human hematopoietic cell lines, each of which was further categorized into cell-type-specific (GM12878- and K562-specific) and shared binding sites. Then, multiple types of features for these binding sites were integrated to train the XGBoost- and CNN-based models. Experimental results show that our proposed approaches significantly outperform other competing methods on three classification tasks. Moreover, we identified independent feature contributions for cell-type-specific and shared sites through SHAP values and explored the ability of the CNN-based model to predict cell-type-specific and shared binding sites by excluding or including DNase signals. Furthermore, we investigated the generalization ability of our proposed approaches to different binding factors in the same cellular environment. AVAILABILITY AND IMPLEMENTATION: The source code is available at: https://github.com/turningpoint1988/CSSBS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Using Fully Convolutional Network to Locate Transcription Factor Binding Sites Based on DNA Sequence and Conservation Information.

Transcription factors (TFs) play a part in gene expression. TFs can form complex gene expression regulation system by combining with DNA. Thereby, identifying the binding regions has become an indispensable step for understanding the regulatory mechanism of gene expression. Due to the great achievements of applying deep learning (DL) to computer vision and language processing in recent years, many scholars are inspired to use these methods to predict TF binding sites (TFBSs), achieving extraordinary results. However, these methods mainly focus on whether DNA sequences include TFBSs. In this paper, we propose a fully convolutional network (FCN) coupled with refinement residual block (RRB) and global average pooling layer (GAPL), namely FCNARRB. Our model could classify binding sequences at nucleotide level by outputting dense label for input data. Experimental results on human ChIP-seq datasets show that the RRB and GAPL structures are very useful for improving model performance. Adding GAPL improves the performance by 9.32% and 7.61% in terms of IoU (Intersection of Union) and PRAUC (Area Under Curve of Precision and Recall), and adding RRB improves the performance by 7.40% and 4.64%, respectively. In addition, we find that conservation information can help locate TFBSs.

DLoopCaller: A deep learning approach for predicting genome-wide chromatin loops by integrating accessible chromatin landscapes.

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.

Base-resolution prediction of transcription factor binding signals by a deep learning framework.

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.

Predicting In-Vitro DNA-Protein Binding With a Spatially Aligned Fusion of Sequence and Shape.

Discovery of transcription factor binding sites (TFBSs) is of primary importance for understanding the underlying binding mechanic and gene regulation process. Growing evidence indicates that apart from the primary DNA sequences, DNA shape landscape has a significant influence on transcription factor binding preference. To effectively model the co-influence of sequence and shape features, we emphasize the importance of position information of sequence motif and shape pattern. In this paper, we propose a novel deep learning-based architecture, named hybridShape eDeepCNN, for TFBS prediction which integrates DNA sequence and shape information in a spatially aligned manner. Our model utilizes the power of the multi-layer convolutional neural network and constructs an independent subnetwork to adapt for the distinct data distribution of heterogeneous features. Besides, we explore the usage of continuous embedding vectors as the representation of DNA sequences. Based on the experiments on 20 in-vitro datasets derived from universal protein binding microarrays (uPBMs), we demonstrate the superiority of our proposed method and validate the underlying design logic.

FCNGRU: Locating Transcription Factor Binding Sites by Combing Fully Convolutional Neural Network With Gated Recurrent Unit.

Deciphering the relationship between transcription factors (TFs) and DNA sequences is very helpful for computational inference of gene regulation and a comprehensive understanding of gene regulation mechanisms. Transcription factor binding sites (TFBSs) are specific DNA short sequences that play a pivotal role in controlling gene expression through interaction with TF proteins. Although recently many computational and deep learning methods have been proposed to predict TFBSs aiming to predict sequence specificity of TF-DNA binding, there is still a lack of effective methods to directly locate TFBSs. In order to address this problem, we propose FCNGRU combing a fully convolutional neural network (FCN) with the gated recurrent unit (GRU) to directly locate TFBSs in this paper. Furthermore, we present a two-task framework (FCNGRU-double): one is a classification task at nucleotide level which predicts the probability of each nucleotide and locates TFBSs, and the other is a regression task at sequence level which predicts the intensity of each sequence. A series of experiments are conducted on 45 in-vitro datasets collected from the UniPROBE database derived from universal protein binding microarrays (uPBMs). Compared with competing methods, FCNGRU-double achieves much better results on these datasets. Moreover, FCNGRU-double has an advantage over a single-task framework, FCNGRU-single, which only contains the branch of locating TFBSs. In addition, we combine with in vivo datasets to make a further analysis and discussion.

Predicting transcription factor binding sites using DNA shape features based on shared hybrid deep learning architecture.

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.

Locating transcription factor binding sites by fully convolutional neural network.

Transcription factors (TFs) play an important role in regulating gene expression, thus identification of the regions bound by them has become a fundamental step for molecular and cellular biology. In recent years, an increasing number of deep learning (DL) based methods have been proposed for predicting TF binding sites (TFBSs) and achieved impressive prediction performance. However, these methods mainly focus on predicting the sequence specificity of TF-DNA binding, which is equivalent to a sequence-level binary classification task, and fail to identify motifs and TFBSs accurately. In this paper, we developed a fully convolutional network coupled with global average pooling (FCNA), which by contrast is equivalent to a nucleotide-level binary classification task, to roughly locate TFBSs and accurately identify motifs. Experimental results on human ChIP-seq datasets show that FCNA outperforms other competing methods significantly. Besides, we find that the regions located by FCNA can be used by motif discovery tools to further refine the prediction performance. Furthermore, we observe that FCNA can accurately identify TF-DNA binding motifs across different cell lines and infer indirect TF-DNA bindings.

A survey on deep learning in DNA/RNA motif mining.

DNA/RNA motif mining is the foundation of gene function research. The DNA/RNA motif mining plays an extremely important role in identifying the DNA- or RNA-protein binding site, which helps to understand the mechanism of gene regulation and management. For the past few decades, researchers have been working on designing new efficient and accurate algorithms for mining motif. These algorithms can be roughly divided into two categories: the enumeration approach and the probabilistic method. In recent years, machine learning methods had made great progress, especially the algorithm represented by deep learning had achieved good performance. Existing deep learning methods in motif mining can be roughly divided into three types of models: convolutional neural network (CNN) based models, recurrent neural network (RNN) based models, and hybrid CNN-RNN based models. We introduce the application of deep learning in the field of motif mining in terms of data preprocessing, features of existing deep learning architectures and comparing the differences between the basic deep learning models. Through the analysis and comparison of existing deep learning methods, we found that the more complex models tend to perform better than simple ones when data are sufficient, and the current methods are relatively simple compared with other fields such as computer vision, language processing (NLP), computer games, etc. Therefore, it is necessary to conduct a summary in motif mining by deep learning, which can help researchers understand this field.

Identification of Essential Proteins Based on Improved HITS Algorithm.

Essential proteins are critical to the development and survival of cells. Identifying and analyzing essential proteins is vital to understand the molecular mechanisms of living cells and design new drugs. With the development of high-throughput technologies, many protein⁻protein interaction (PPI) data are available, which facilitates the studies of essential proteins at the network level. Up to now, although various computational methods have been proposed, the prediction precision still needs to be improved. In this paper, we propose a novel method by applying Hyperlink-Induced Topic Search (HITS) on weighted PPI networks to detect essential proteins, named HSEP. First, an original undirected PPI network is transformed into a bidirectional PPI network. Then, both biological information and network topological characteristics are taken into account to weighted PPI networks. Pieces of biological information include gene expression data, Gene Ontology (GO) annotation and subcellular localization. The edge clustering coefficient is represented as network topological characteristics to measure the closeness of two connected nodes. We conducted experiments on two species, namely Saccharomyces cerevisiae and Drosophila melanogaster, and the experimental results show that HSEP outperformed some state-of-the-art essential proteins detection techniques.