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.

Synthetic lethality (SL) is a novel strategy for anticancer therapies, whereby mutations of two genes will kill a cell but mutation of a single gene will not. Therefore, a cancer-specific mutation combined with a drug-induced mutation, if they have SL interactions, will selectively kill cancer cells. While numerous SL interactions have been identified in yeast, only a few have been known in human. There is a pressing need to systematically discover and understand SL interactions specific to human cancer. In this paper, we present Syn-Lethality, the first integrative knowledge base of SL that is dedicated to human cancer. It integrates experimentally discovered and verified human SL gene pairs into a network, associated with annotations of gene functions, pathways and molecular mechanisms. It also includes yeast SL genes from high-throughput screenings which are mapped to orthologous human genes. Such an integrative knowledge base, organized as a relational database with user interface for searching and network visualization, will greatly expedite the discovery of novel anticancer drug targets based on synthetic lethality interactions. The database can be downloaded as a stand-alone Java application from: http://www.ntu.edu.sg/home/zhengjie/software/Syn-Lethality/.