Accurately reconstructing gene regulatory networks (GRNs) from high-throughput gene expression data has been a major challenge in systems biology for decades. Many approaches have been proposed to solve this problem. However, there is still much room for the improvement of GRN inference. Integrating data from different sources is a promising strategy. Epigenetic modifications have a close relationship with gene regulation. Hence, epigenetic data such as histone modification profiles can provide useful information for uncovering regulatory interactions between genes. In this paper, we propose a method to integrate epigenetic data into the inference of GRNs. In particular, a dynamic Bayesian network (DBN) is employed to infer gene regulations from time-series gene expression data. Epigenetic data (histone modification profiles here) are integrated into the prior probability distribution of the Bayesian model. Our method has been validated on both synthetic and real datasets. Experimental results show that the integration of epigenetic data can significantly improve the performance of GRN inference. As more epigenetic datasets become available, our method would be useful for elucidating the gene regulatory mechanisms driving various cellular activities. The source code and testing datasets are available at https://github.com/Zheng-Lab/MetaGRN/tree/master/histonePrior.

Accurately reconstructing gene regulatory network (GRN) from gene expression data is a challenging task in systems biology. Although some progresses have been made, the performance of GRN reconstruction still has much room for improvement. Because many regulatory events are asynchronous, learning gene interactions with multiple time delays is an effective way to improve the accuracy of GRN reconstruction. Here, we propose a new approach, called Max-Min high-order dynamic Bayesian network (MMHO-DBN) by extending the Max-Min hill-climbing Bayesian network technique originally devised for learning a Bayesian network's structure from static data. Our MMHO-DBN can explicitly model the time lags between regulators and targets in an efficient manner. It first uses constraint-based ideas to limit the space of potential structures, and then applies search-and-score ideas to search for an optimal HO-DBN structure. The performance of MMHO-DBN to GRN reconstruction was evaluated using both synthetic and real gene expression time-series data. Results show that MMHO-DBN is more accurate than current time-delayed GRN learning methods, and has an intermediate computing performance. Furthermore, it is able to learn long time-delayed relationships between genes. We applied sensitivity analysis on our model to study the performance variation along different parameter settings. The result provides hints on the setting of parameters of MMHO-DBN.

MOTIVATION: Transcriptional regulatory networks controlling cell fate decisions in mammalian embryonic development remain elusive despite a long time of research. The recent emergence of single-cell RNA profiling technology raises hope for new discovery. Although experimental works have obtained intriguing insights into the mouse early development, a holistic and systematic view is still missing. Mathematical models of cell fates tend to be concept-based, not designed to learn from real data. To elucidate the regulatory mechanisms behind cell fate decisions, it is highly desirable to synthesize the data-driven and knowledge-driven modeling approaches. RESULTS: We propose a novel method that integrates the structure of a cell lineage tree with transcriptional patterns from single-cell data. This method adopts probabilistic Boolean network (PBN) for network modeling, and genetic algorithm as search strategy. Guided by the 'directionality' of cell development along branches of the cell lineage tree, our method is able to accurately infer the regulatory circuits from single-cell gene expression data, in a holistic way. Applied on the single-cell transcriptional data of mouse preimplantation development, our algorithm outperforms conventional methods of network inference. Given the network topology, our method can also identify the operational interactions in the gene regulatory network (GRN), corresponding to specific cell fate determination. This is one of the first attempts to infer GRNs from single-cell transcriptional data, incorporating dynamics of cell development along a cell lineage tree. AVAILABILITY AND IMPLEMENTATION: Implementation of our algorithm is available from the authors upon request. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gene regulatory network (GRN) inference from high throughput biological data has drawn a lot of research interest in the last decade. However, due to the complexity of gene regulation and lack of sufficient data, GRN inference still has much space to improve. One way to improve the inference of GRN is by developing methods to accurately combine various types of data. Here we apply dynamic Bayesian network (DBN) to infer GRN from time-series gene expression data where the Bayesian prior is derived from epigenetic data of histone modifications. We propose several kinds of prior from histone modification data, and use both real and synthetic data to compare their performance. Parameters of prior integration are also studied to achieve better results. Experiments on gene expression data of yeast cell cycle show that our methods increase the accuracy of GRN inference significantly.