TY - JOUR T1 - Identification of <em>cis</em> elements for spatio-temporal control of DNA replication JF - bioRxiv DO - 10.1101/285650 SP - 285650 AU - Jiao Sima AU - Abhijit Chakraborty AU - Vishnu Dileep AU - Marco Michalski AU - Juan Carlos Rivera-Mulia AU - Claudia Trevilla-Garcia AU - Kyle N. Klein AU - Daniel Bartlett AU - Brian K. Washburn AU - Michelle T. Paulsen AU - Daniel Vera AU - Elphège P. Nora AU - Katerina Kraft AU - Stefan Mundlos AU - Benoit G. Bruneau AU - Mats Ljungman AU - Peter Fraser AU - Ferhat Ay AU - David M. Gilbert Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/03/21/285650.abstract N2 - The temporal order of DNA replication (replication timing, RT) is highly coupled with genome architecture, but cis-elements regulating spatio-temporal control of replication have remained elusive. We performed an extensive series of CRISPR mediated deletions and inversions and high-resolution capture Hi-C of a pluripotency associated domain (DppA2/4) in mouse embryonic stem cells. Whereas CTCF mediated loops and chromatin domain boundaries were dispensable, deletion of three intra-domain prominent CTCF-independent 3D contact sites caused a domain-wide delay in RT, shift in sub-nuclear chromatin compartment and loss of transcriptional activity, These “early replication control elements” (ERCEs) display prominent chromatin features resembling enhancers/promoters and individual and pair-wise deletions of the ERCEs confirmed their partial redundancy and interdependency in controlling domain-wide RT and transcription. Our results demonstrate that discrete cis-regulatory elements mediate domain-wide RT, chromatin compartmentalization, and transcription, representing a major advance in dissecting the relationship between genome structure and function.Highlightscis-elements (ERCEs) regulate large scale chromosome structure and functionMultiple ERCEs cooperatively control domain-wide replicationERCEs harbor prominent active chromatin features and form CTCF-independent loopsERCEs enable genetic dissection of large-scale chromosome structure-function. ER -