Phenotypic Drug Discovery enables the exploration and identification of new compounds with potential therapeutic value without the need to predefine the molecular targets of drug action or hypothesize their mechanisms in pathology. Chemicalinduced transcriptional profiles offer a comprehensive view of phenotypic responses to drugs and serve as a key tool in phenotype-based compound screening. Hence, it is necessary to develop an algorithm for predicting chemical-induced transcription profiles. Existing works tried to predict the transcription profile based on the structure of a compound, but the results are not yet satisfactory. Transcriptional profiles during the induction process are influenced not only by the structural features of compounds, cellular context, and dosages but also by the complex interactions between compounds and biological entities (e.g. target, diseases, and side effects) and the physicochemical properties of compounds. Here, we propose a deep learning model called IDCLP to predict gene expression profiles induced by de novo compounds. It utilizes a heterogeneous graph attention mechanism for extracting drug embedding and integrates the similarity network fusion algorithm to construct a drug similarity network. Moreover, IDCLP utilizes attention mechanisms to model the associations between drugs and cell lines. Experimental results show that IDCLP outperforms state-of-the-art methods, especially with unseen drugs that are dissimilar from the drugs in the supervised learning. Our implementation of IDCLP is available at https://github.com/sdesignates/IDCLP.git.

Recent advances in single-cell RNA sequencing (scRNA-seq) technology provides unprecedented opportunities for reconstruction gene regulation networks (GRNs). At present, many different models have been proposed to infer GRN from a large number of RNA-seq data, but most deep learning models use a priori gene regulatory network to infer potential GRNs. It is a challenge to reconstruct GRNs from scRNA-seq data due to the noise and sparsity introduced by the dropout effect. Here, we propose GAALink, a novel unsupervised deep learning method. It first constructs the gene similarity matrix and then refines it by threshold value. It then learns feature representations of genes through a graphical attention autoencoder that propagates information across genes with different weights. Finally, we use gene feature expression for matrix completion such that the GRNs are reconstructed. Compared with seven existing GRNs reconstruction methods, GAALink achieves more accurate performance on seven scRNA-seq dataset with four ground truth networks. GAALink can provide a useful tool for inferring GRNs for scRNA-seq expression data.

Single-cell RNA-sequencing (scRNA-seq) has emerged as a powerful technique for studying gene expression patterns at the single-cell level. Inferring gene regulatory networks (GRNs) from scRNA-seq data provides insight into cellular phenotypes from the genomic level. However, the high sparsity, noise and dropout events inherent in scRNA-seq data present challenges for GRN inference. In recent years, the dramatic increase in data on experimentally validated transcription factors binding to DNA has made it possible to infer GRNs by supervised methods. In this study, we address the problem of GRN inference by framing it as a graph link prediction task. In this paper, we propose a novel framework called GNNLink, which leverages known GRNs to deduce the potential regulatory interdependencies between genes. First, we preprocess the raw scRNA-seq data. Then, we introduce a graph convolutional network-based interaction graph encoder to effectively refine gene features by capturing interdependencies between nodes in the network. Finally, the inference of GRN is obtained by performing matrix completion operation on node features. The features obtained from model training can be applied to downstream tasks such as measuring similarity and inferring causality between gene pairs. To evaluate the performance of GNNLink, we compare it with six existing GRN reconstruction methods using seven scRNA-seq datasets. These datasets encompass diverse ground truth networks, including functional interaction networks, Loss of Function/Gain of Function data, non-specific ChIP-seq data and cell-type-specific ChIP-seq data. Our experimental results demonstrate that GNNLink achieves comparable or superior performance across these datasets, showcasing its robustness and accuracy. Furthermore, we observe consistent performance across datasets of varying scales. For reproducibility, we provide the data and source code of GNNLink on our GitHub repository: https://github.com/sdesignates/GNNLink.

BACKGROUND: Building biological networks with a certain function is a challenge in systems biology. For the functionality of small (less than ten nodes) biological networks, most methods are implemented by exhausting all possible network topological spaces. This exhaustive approach is difficult to scale to large-scale biological networks. And regulatory relationships are complex and often nonlinear or non-monotonic, which makes inference using linear models challenging. RESULTS: In this paper, we propose a multi-layer perceptron-based differential equation method, which operates by training a fully connected neural network (NN) to simulate the transcription rate of genes in traditional differential equations. We verify whether the regulatory network constructed by the NN method can continue to achieve the expected biological function by verifying the degree of overlap between the regulatory network discovered by NN and the regulatory network constructed by the Hill function. And we validate our approach by adapting to noise signals, regulator knockout, and constructing large-scale gene regulatory networks using link-knockout techniques. We apply a real dataset (the mesoderm inducer Xenopus Brachyury expression) to construct the core topology of the gene regulatory network and find that Xbra is only strongly expressed at moderate levels of activin signaling. CONCLUSION: We have demonstrated from the results that this method has the ability to identify the underlying network topology and functional mechanisms, and can also be applied to larger and more complex gene network topologies.