PT  - JOURNAL ARTICLE
AU  - Juan Carlos Rivera-Mulia
AU  - Sebo Kim
AU  - Haitham Gabr
AU  - Abhijit Chakraborty
AU  - Ferhat Ay
AU  - Tamer Kahveci
AU  - David M. Gilbert
TI  - Replication Timing Networks: a novel class of gene regulatory networks
AID  - 10.1101/186866
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 186866
4099  - http://biorxiv.org/content/early/2018/12/09/186866.short
4100  - http://biorxiv.org/content/early/2018/12/09/186866.full
AB  - 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 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 transcriptional regulatory networks (TRNs), by combining them into more complex circuitries of composite and bipartite networks, revealing novel trans interactions between transcription factors and downstream RT changes that were validated with ChIP-seq data. Our findings suggest a regulatory link between the establishment of cell type specific TRNs and RT control during lineage specification.