University of Michigan at Ann Arbor - Department of Pathology; University of Michigan at Ann Arbor - Department of Environmental Health Sciences; University of Michigan at Ann Arbor - Center for RNA Biomedicine
University of California, San Francisco (UCSF) - Gladstone Institute of Cardiovascular Disease; University of California, San Francisco (UCSF) - Roddenberry Center for Stem Cell Biology and Medicine; University of California, San Francisco (UCSF) - Department of Pediatrics; University of California, San Francisco (UCSF) - Cardiovascular Research Institute
Max Planck Society for the Advancement of the Sciences - Rearch Group Development & Disease; Charité - Universitätsmedizin Berlin - Institute for Medical and Human Genetics
Max Planck Society for the Advancement of the Sciences - Rearch Group Development & Disease; Charité - Universitätsmedizin Berlin - Institute for Medical and Human Genetics
University of California, San Francisco (UCSF) - Gladstone Institute of Cardiovascular Disease; University of California, San Francisco (UCSF) - Roddenberry Center for Stem Cell Biology and Medicine; University of California, San Francisco (UCSF) - Department of Pediatrics; University of California, San Francisco (UCSF) - Cardiovascular Research Institute
University of Michigan at Ann Arbor - Department of Radiation Oncology; University of Michigan at Ann Arbor - Department of Environmental Health Sciences; University of Michigan at Ann Arbor - Center for RNA Biomedicine
Florida State University - Department of Biological Science; The Babraham Institute - Nuclear Dynamics Program; Florida State University - Center for Genomics and Personalized Medicine
The temporal order of DNA replication (replication timing, RT) is highly coupled with genome architecture, but cis-elements regulating spatio-temporal control of replicatio 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.
Sima, Jiao and Chakraborty, Abhijit and Dileep, Vishnu and Michalski, Marco and Rivera-Mulia, Juan Carlos and Trevilla-Garcia, Claudia and Klein, Kyle N. and Bartlett, Daniel and Washburn, Brian K. and Paulsen, Michelle T. and Vera, Daniel and Nora, Elphège P. and Kraft, Katerina and Mundlos, Stefan and Bruneau, Benoit G. and Ljungman, Mats and Fraser, Peter and Ay, Ferhat and Gilbert, David M., Identification of cis Elements for Spatio-temporal Control of DNA Replication (2018). Available at SSRN: https://ssrn.com/abstract=3188454 or http://dx.doi.org/10.2139/ssrn.3188454
This version of the paper has not been formally peer reviewed.
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