Quantitative detection of histone modifications has emerged in the recent years as a major means for understanding such biological processes as chromosome packaging, transcriptional activation, and DNA damage. However, high-throughput experimental techniques such as ChIP-seq are usually expensive and time-consuming, prohibiting the establishment of a histone modification landscape for hundreds of cell types across dozens of histone markers. These disadvantages have been appealing for computational methods to complement experimental approaches towards large-scale analysis of histone modifications. We proposed a deep learning framework to integrate sequence information and chromatin accessibility data for the accurate prediction of modification sites specific to different histone markers. Our method, named DeepHistone, outperformed several baseline methods in a series of comprehensive validation experiments, not only within an epigenome but also across epigenomes. Besides, sequence signatures automatically extracted by our method was consistent with known transcription factor binding sites, thereby giving insights into regulatory signatures of histone modifications. As an application, our method was shown to be able to distinguish functional single nucleotide polymorphisms from their nearby genetic variants, thereby having the potential to be used for exploring functional implications of putative disease-associated genetic variants. DeepHistone demonstrated the possibility of using a deep learning framework to integrate DNA sequence and experimental data for predicting epigenomic signals. With the state-of-the-art performance, DeepHistone was expected to shed light on a variety of epigenomic studies. DeepHistone is freely available in https://github.com/QijinYin/DeepHistone .

Detecting cancer signals in cell-free DNA (cfDNA) high-throughput sequencing data is emerging as a novel noninvasive cancer detection method. Due to the high cost of sequencing, it is crucial to make robust and precise predictions with low-depth cfDNA sequencing data. Here we propose a novel approach named DISMIR, which can provide ultrasensitive and robust cancer detection by integrating DNA sequence and methylation information in plasma cfDNA whole-genome bisulfite sequencing (WGBS) data. DISMIR introduces a new feature termed as ‘switching region’ to define cancer-specific differentially methylated regions, which can enrich the cancer-related signal at read-resolution. DISMIR applies a deep learning model to predict the source of every single read based on its DNA sequence and methylation state and then predicts the risk that the plasma donor is suffering from cancer. DISMIR exhibited high accuracy and robustness on hepatocellular carcinoma detection by plasma cfDNA WGBS data even at ultralow sequencing depths. Further analysis showed that DISMIR tends to be insensitive to alterations of single CpG sites’ methylation states, which suggests DISMIR could resist to technical noise of WGBS. All these results showed DISMIR with the potential to be a precise and robust method for low-cost early cancer detection.

Single-cell technologies play a crucial role in revolutionizing biological research over the past decade, which strengthens our understanding in cell differentiation, development and regulation from a single-cell level perspective. Single-cell RNA sequencing (scRNA-seq) is one of the most common single cell technologies, which enables probing transcriptional states in thousands of cells in one experiment. Identification of cell types from scRNA-seq measurements is a fundamental and crucial question to answer. Most previous studies directly take gene expression as input while ignoring the comprehensive gene–gene interactions. We propose scGraph, an automatic cell identification algorithm leveraging gene interaction relationships to enhance the performance of the cell-type identification. scGraph is based on a graph neural network to aggregate the information of interacting genes. In a series of experiments, we demonstrate that scGraph is accurate and outperforms eight comparison methods in the task of cell-type identification. Moreover, scGraph automatically learns the gene interaction relationships from biological data and the pathway enrichment analysis shows consistent findings with previous analysis, providing insights on the analysis of regulatory mechanism. scGraph is freely available at https://github.com/QijinYin/scGraph and https://figshare.com/articles/software/scGraph/17157743. Supplementary data are available at Bioinformatics online.

The establishment of a landscape of enhancers across human cells is crucial to deciphering the mechanism of gene regulation, cell differentiation, and disease development. High-throughput experimental approaches, which contain successfully reported enhancers in typical cell lines, are still too costly and time-consuming to perform systematic identification of enhancers specific to different cell lines. Existing computational methods, capable of predicting regulatory elements purely relying on DNA sequences, lack the power of cell line-specific screening. Recent studies have suggested that chromatin accessibility of a DNA segment is closely related to its potential function in regulation, and thus may provide useful information in identifying regulatory elements. Motivated by the aforementioned understanding, we integrate DNA sequences and chromatin accessibility data to accurately predict enhancers in a cell line-specific manner. We proposed DeepCAPE, a deep convolutional neural network to predict enhancers via the integration of DNA sequences and DNase-seq data. Benefitting from the well-designed feature extraction mechanism and skip connection strategy, our model not only consistently outperforms existing methods in the imbalanced classification of cell line-specific enhancers against background sequences, but also has the ability to self-adapt to different sizes of datasets. Besides, with the adoption of auto-encoder, our model is capable of making cross-cell line predictions. We further visualize kernels of the first convolutional layer and show the match of identified sequence signatures and known motifs. We finally demonstrate the potential ability of our model to explain functional implications of putative disease-associated genetic variants and discriminate disease-related enhancers. The source code and detailed tutorial of DeepCAPE are freely available at https://github.com/ShengquanChen/DeepCAPE.