A novel convolution attention model for predicting transcription factor binding sites by combination of sequence and shape.

The discovery of putative transcription factor binding sites (TFBSs) is important for understanding the underlying binding mechanism and cellular functions. Recently, many computational methods have been proposed to jointly account for DNA sequence and shape properties in TFBSs prediction. However, these methods fail to fully utilize the latent features derived from both sequence and shape profiles and have limitation in interpretability and knowledge discovery. To this end, we present a novel Deep Convolution Attention network combining Sequence and Shape, dubbed as D-SSCA, for precisely predicting putative TFBSs. Experiments conducted on 165 ENCODE ChIP-seq datasets reveal that D-SSCA significantly outperforms several state-of-the-art methods in predicting TFBSs, and justify the utility of channel attention module for feature refinements. Besides, the thorough analysis about the contribution of five shapes to TFBSs prediction demonstrates that shape features can improve the predictive power for transcription factors-DNA binding. Furthermore, D-SSCA can realize the cross-cell line prediction of TFBSs, indicating the occupancy of common interplay patterns concerning both sequence and shape across various cell lines. The source code of D-SSCA can be found at https://github.com/MoonLord0525/.

HAMPLE: deciphering TF-DNA binding mechanism in different cellular environments by characterizing higher-order nucleotide dependency.

MOTIVATION: Transcription factor (TF) binds to conservative DNA binding sites in different cellular environments and development stages by physical interaction with interdependent nucleotides. However, systematic computational characterization of the relationship between higher-order nucleotide dependency and TF-DNA binding mechanism in diverse cell types remains challenging. RESULTS: Here, we propose a novel multi-task learning framework HAMPLE to simultaneously predict TF binding sites (TFBS) in distinct cell types by characterizing higher-order nucleotide dependencies. Specifically, HAMPLE first represents a DNA sequence through three higher-order nucleotide dependencies, including k-mer encoding, DNA shape and histone modification. Then, HAMPLE uses the customized gate control and the channel attention convolutional architecture to further capture cell-type-specific and cell-type-shared DNA binding motifs and epigenomic languages. Finally, HAMPLE exploits the joint loss function to optimize the TFBS prediction for different cell types in an end-to-end manner. Extensive experimental results on seven datasets demonstrate that HAMPLE significantly outperforms the state-of-the-art approaches in terms of auROC. In addition, feature importance analysis illustrates that k-mer encoding, DNA shape, and histone modification have predictive power for TF-DNA binding in different cellular environments and are complementary to each other. Furthermore, ablation study, and interpretable analysis validate the effectiveness of the customized gate control and the channel attention convolutional architecture in characterizing higher-order nucleotide dependencies. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/ZhangLab312/Hample.

Multiple sequence alignment based on deep reinforcement learning with self-attention and positional encoding.

MOTIVATION: Multiple sequence alignment (MSA) is one of the hotspots of current research and is commonly used in sequence analysis scenarios. However, there is no lasting solution for MSA because it is a Nondeterministic Polynomially complete problem, and the existing methods still have room to improve the accuracy. RESULTS: We propose Deep reinforcement learning with Positional encoding and self-Attention for MSA, based on deep reinforcement learning, to enhance the accuracy of the alignment Specifically, inspired by the translation technique in natural language processing, we introduce self-attention and positional encoding to improve accuracy and reliability. Firstly, positional encoding encodes the position of the sequence to prevent the loss of nucleotide position information. Secondly, the self-attention model is used to extract the key features of the sequence. Then input the features into a multi-layer perceptron, which can calculate the insertion position of the gap according to the features. In addition, a novel reinforcement learning environment is designed to convert the classic progressive alignment into progressive column alignment, gradually generating each column's sub-alignment. Finally, merge the sub-alignment into the complete alignment. Extensive experiments based on several datasets validate our method's effectiveness for MSA, outperforming some state-of-the-art methods in terms of the Sum-of-pairs and Column scores. AVAILABILITY AND IMPLEMENTATION: The process is implemented in Python and available as open-source software from https://github.com/ZhangLab312/DPAMSA.

Local augmented graph neural network for multi-omics cancer prognosis prediction and analysis.

Cancer prognosis prediction and analysis can help patients understand expected life and help clinicians provide correct therapeutic guidance. Thanks to the development of sequencing technology, multi-omics data, and biological networks have been used for cancer prognosis prediction. Besides, graph neural networks can simultaneously consider multi-omics features and molecular interactions in biological networks, becoming mainstream in cancer prognosis prediction and analysis. However, the limited number of neighboring genes in biological networks restricts the accuracy of graph neural networks. To solve this problem, a local augmented graph convolutional network named LAGProg is proposed in this paper for cancer prognosis prediction and analysis. The process follows: first, given a patient's multi-omics data features and biological network, the corresponding augmented conditional variational autoencoder generates features. Then, the generated augmented features and the original features are fed into a cancer prognosis prediction model to complete the cancer prognosis prediction task. The conditional variational autoencoder consists of two parts: encoder-decoder. In the encoding phase, an encoder learns the conditional distribution of the multi-omics data. As a generative model, a decoder takes the conditional distribution and the original feature as inputs to generate the enhanced features. The cancer prognosis prediction model consists of a two-layer graph convolutional neural network and a Cox proportional risk network. The Cox proportional risk network consists of fully connected layers. Extensive experiments on 15 real-world datasets from TCGA demonstrated the effectiveness and efficiency of the proposed method in predicting cancer prognosis. LAGProg improved the C-index values by an average of 8.5% over the state-of-the-art graph neural network method. Moreover, we confirmed that the local augmentation technique could enhance the model's ability to represent multi-omics features, improve the model's robustness to missing multi-omics features, and prevent the model's over-smoothing during training. Finally, based on genes identified through differential expression analysis, we discovered 13 prognostic markers highly associated with breast cancer, among which ten genes have been proved by literature review.

MetaSEM: Gene Regulatory Network Inference from Single-Cell RNA Data by Meta-Learning.

Regulators in gene regulatory networks (GRNs) are crucial for identifying cell states. However, GRN inference based on scRNA-seq data has several problems, including high dimensionality and sparsity, and requires more label data. Therefore, we propose a meta-learning GRN inference framework to identify regulatory factors. Specifically, meta-learning solves the parameter optimization problem caused by high-dimensional sparse data features. In addition, a few-shot solution was used to solve the problem of lack of label data. A structural equation model (SEM) was embedded in the model to identify important regulators. We integrated the parameter optimization strategy into the bi-level optimization to extract the feature consistent with GRN reasoning. This unique design makes our model robust to small-scale data. By studying the GRN inference task, we confirmed that the selected regulators were closely related to gene expression specificity. We further analyzed the GRN inferred to find the important regulators in cell type identification. Extensive experimental results showed that our model effectively captured the regulator in single-cell GRN inference. Finally, the visualization results verified the importance of the selected regulators for cell type recognition.

Towards a better understanding of TF-DNA binding prediction from genomic features.

Transcription factors (TFs) can regulate gene expression by recognizing specific cis-regulatory elements in DNA sequences. TF-DNA binding prediction has become a fundamental step in comprehending the underlying cis-regulation mechanism. Since a particular genome region is bound depending on multiple features, such as the arrangement of nucleotides, DNA shape, and an epigenetic mechanism, many researchers attempt to develop computational methods to predict TF binding sites (TFBSs) based on various genomic features. This paper provides a comprehensive compendium to better understand TF-DNA binding from genomic features. We first summarize the commonly used datasets and data processing manners. Subsequently, we classify current deep learning methods in TFBS prediction according to their utilized genomic features and analyze each technique's merit and weakness. Furthermore, we illustrate the functional consequences characterization of TF-DNA binding by prioritizing noncoding variants in identified motif instances. Finally, the challenges and opportunities of deep learning in TF-DNA binding prediction are discussed. This survey can bring valuable insights for researchers to study the modeling of TF-DNA binding.

Uncovering the Relationship between Tissue-Specific TF-DNA Binding and Chromatin Features through a Transformer-Based Model.

Chromatin features can reveal tissue-specific TF-DNA binding, which leads to a better understanding of many critical physiological processes. Accurately identifying TF-DNA bindings and constructing their relationships with chromatin features is a long-standing goal in the bioinformatic field. However, this has remained elusive due to the complex binding mechanisms and heterogeneity among inputs. Here, we have developed the GHTNet (General Hybrid Transformer Network), a transformer-based model to predict TF-DNA binding specificity. The GHTNet decodes the relationship between tissue-specific TF-DNA binding and chromatin features via a specific input scheme of alternative inputs and reveals important gene regions and tissue-specific motifs. Our experiments show that the GHTNet has excellent performance, achieving about a 5% absolute improvement over existing methods. The TF-DNA binding mechanism analysis shows that the importance of TF-DNA binding features varies across tissues. The best predictor is based on the DNA sequence, followed by epigenomics and shape. In addition, cross-species studies address the limited data, thus providing new ideas in this case. Moreover, the GHTNet is applied to interpret the relationship among TFs, chromatin features, and diseases associated with AD46 tissue. This paper demonstrates that the GHTNet is an accurate and robust framework for deciphering tissue-specific TF-DNA binding and interpreting non-coding regions.