Replication timing networks reveal a link between transcription regulatory circuits and replication timing control

Abstract

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.

The Fkh1 Forkhead Associated Domain Promotes ORC Binding to a Subset of DNA Replication Origins in Budding Yeast

“…If this explanation were correct, then fkh1Δ FKH2 cells should show no defect in ARS1529.5 activity because, in the complete absence of Fkh1,Fkh2 should now be able to bind the 5' FKH site. Consistent with this explanation, fkh1∆ cells replicated ARS1529 5.…”

“…These data provided in vivo evidence that the Fkh1-FHA domain promoted ARS1529.5 activity by binding to the ARS1529. 5 5' FKH site.…”

“…Thus, some origins act more efficiently and earlier in S-phase than others. These differences in origin activation probabilities generate a spatiotemporal pattern of genome duplication with relevance to genome stability and cell function [1][2][3][4][5]. Because chromatin heterogeneity is essential for the structure and function of chromosomes, each individual origin must act within a distinct local chromatin environment.…”

Expanded encyclopaedias of DNA elements in the human and mouse genomes

“…The analysis of these data sets revealed that the developmental lineage of each cell type could be recapitulated on the basis of its replication timing. ENCODE replication timing data have also been used to build background mutation models to study the somatic mutation process 38 and to construct novel, cell type-specific regulatory networks 39 .…”

Understanding and Engineering Chromatin as a Dynamical System across Length and Timescales

“…The local and global state of chromatin is dynamically altered through a combination of induced forces, torques, and chemical alterations which both operate on, and bridge, the respective length and timescales of cellular function (see Box 1). These effects provide a scaffold for epigenetic memory and a channel for information transmission that must work collectively for the emergence of spatial and temporal fidelity of crucial cellular functions such as replication and transcription (Rivera-Mulia et al, 2019). Gaps remain in our understanding of how transcription and transcriptional regulation impact structures to enable the emergence of new transcriptional states.…”