Identification of cis elements for spatio-temporal control of DNA replication

Jiao Sima, Abhijit Chakraborty, Vishnu Dileep, Marco Michalski, Juan Carlos Rivera-Mulia, Claudia Trevilla-Garcia, Kyle N Klein, Daniel Bartlett, Brian K Washburn, Michelle T Paulsen, Daniel Vera, Elphège P Nora, Katerina Kraft, Stefan Mundlos, Benoit G Bruneau, Mats Ljungman, Peter Fraser, Ferhat Ay, David M Gilbert

Research output: Contribution to journalArticle

Abstract

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 early to late switch 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.
Original languageEnglish (US)
Pages (from-to)285650
Number of pages1
JournalbioRxiv
DOIs
StatePublished - 2018

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