DNA replication occurs in a defined temporal order known as the replication timing (RT) program and is regulated during development, coordinated with 3D genome organization and transcriptional activity. However, transcription and RT are not sufficiently coordinated to predict each other, suggesting an indirect relationship. Here, we exploit genome-wide RT profiles from 15 human cell types and intermediate differentiation stages derived from human embryonic stem cells to construct different types of RT regulatory networks. First, we constructed networks based on the coordinated RT changes during cell fate commitment to create highly complex RT networks composed of thousands of interactions that form specific functional subnetwork communities. We also constructed directional regulatory networks based on the order of RT changes within cell lineages, and identified master regulators of differentiation pathways. Finally, we explored relationships between RT networks and transcriptional regulatory networks (TRNs) by combining them into more complex circuitries of composite and bipartite networks. Results identified novel trans interactions linking transcription factors that are core to the regulatory circuitry of each cell type to RT changes occurring in those cell types. These core transcription factors were found to bind cooperatively to sites in the affected replication domains, providing provocative evidence that they constitute biologically significant directional interactions. Our findings suggest a regulatory link between the establishment of cell-type-specific TRNs and RT control during lineage specification.

One of fundamental challenges in cancer studies is that varying molecular characteristics of different tumor types may lead to resistance to certain drugs. As a result, the same drug can lead to significantly different results in different types of cancer thus emphasizing the need for individualized medicine. Individual prediction of drug response has great potential to aid in improving the clinical outcome and reduce the financial costs associated with prescribing chemotherapy drugs to which the patient’s tumor might be resistant. In this paper we develop a network based classifier (NBC) method for predicting sensitivity of cell lines to anticancer drugs from transcriptome data. In the literature, this strategy has been used for predicting cancer types. Here, we extend it to estimate sensitivity of cells from different tumor types to various anticancer drugs. Furthermore, we incorporate domain specific knowledge such as the use of apoptotic gene list and clinical dose information in our method to impart biological significance to the prediction. Our experimental results suggest that our network based classifier (NBC) method outperforms existing classifiers in estimating sensitivity of cell lines for different drugs.

SummaryDNA replication occurs in a defined temporal order known as the replication-timing (RT) program and is regulated during development, coordinated with 3D genome organization and transcriptional activity. Here, we exploit genome-wide RT profiles from 15 human cell types and intermediate differentiation stages derived from human embryonic stem cells to construct 5 different types of RT regulatory networks. First, we constructed networks based on the coordinated RT changes during cell fate commitment to create RT networks composed of specific functional sub-network communities. We also constructed directional regulatory networks based on the order of RT changes within cell lineages and identified master regulators of differentiation pathways. Finally, we explored relationships between RT networks and 10 transcriptional regulatory networks (TRNs), by combining them into more complex circuitries of composite and bipartite networks. Our findings show that RT networks can be exploited to dissect the cellular mechanisms that regulate lineage specification and cellular identity maintenance. 15 Highlights• DNA replication timing (RT) programs were used to construct gene regulatory networks.• RT networks revealed functional organization of sub-network communities. 20• RT networks identified master regulators of cell fate commitment.

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