Replication Timing Networks: a novel class of gene regulatory networks

Abstract

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.

Allele-specific control of replication timing and genome organization during development

“…Additionally, RDs correspond to the topologically associating domains (TADs) measured by chromosome conformation capture techniques, such as Hi-C (Ryba et al 2010;Yaffe et al 2010;Moindrot et al 2012;Pope et al 2014; Rivera-Mulia and Gilbert 2016b). RT is highly conserved in all eukaryotes (Ryba et al 2010;Yue et al 2014;Solovei et al 2016), changes dynamically during development in coordination with changes in nuclear positioning and transcriptional activity (Hiratani et al 2010;Rivera-Mulia et al 2015), and can be exploited to characterize complex circuits of gene regulatory networks (Rivera-Mulia et al 2017b). Hence, RT constitutes a functional readout of genome organization and function.…”

Variable Retention of Differentiation-specific DNA Replication Timing in Human Pediatric Leukemia

“…These ERCEs have prop-330 erties of enhancers but also make strong 3D loops and contain binding sites for core transcriptional regulatory factors. In fact, bipartite networks linking transcription and RT changes during human stem cell differentiation through multiple lineages predicted novel edges (interactions) between core transcriptional regulatory factors and sites within unlinked domains that coordinately change their RT (Rivera-Mulia et al, 2017b). Together, these findings suggest that RT 335 signatures of BCP-ALL may reflect altered cellular transcriptional regulatory networks.…”