Desvendando o mistério de como, quando o DNA replica

segunda-feira, dezembro 31, 2018

Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication

Jiao Sima Abhijit Chakraborty Vishnu Dileep Marco Michalski Kyle N. Klein Nicolas P. Holcomb Jesse L. Turner Michelle T. Paulsen Juan Carlos Rivera-Mulia Claudia Trevilla-Garcia Daniel A. Bartlett Peiyao A. Zhao Brian K. Washburn Elphège P. Nora Katerina Kraft Stefan Mundlos Benoit G. Bruneau Mats Ljungman Peter Fraser Ferhat Ay David M. Gilbert 11

Published: December 27, 2018 DOI:

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• Early replicating control elements (ERCEs) regulate replication timing

• ERCEs regulate A/B compartmentalization and TAD architecture

• ERCEs form CTCF-independent loops and have features of enhancer/promoters

• ERCEs enable genetic dissection of large-scale chromosome structure and function


The temporal order of DNA replication (replication timing [RT]) is highly coupled with genome architecture, but cis-elements regulating either remain elusive. We created a series of CRISPR-mediated deletions and inversions of a pluripotency-associated topologically associating domain (TAD) in mouse ESCs. CTCF-associated domain boundaries were dispensable for RT. CTCF protein depletion weakened most TAD boundaries but had no effect on RT or A/B compartmentalization genome-wide. By contrast, deletion of three intra-TAD CTCF-independent 3D contact sites caused a domain-wide early-to-late RT shift, an A-to-B compartment switch, weakening of TAD architecture, and loss of transcription. The dispensability of TAD boundaries and the necessity of these “early replication control elements” (ERCEs) was validated by deletions and inversions at additional domains. Our results demonstrate that discrete cis-regulatory elements orchestrate domain-wide RT, A/B compartmentalization, TAD architecture, and transcription, revealing fundamental principles linking genome structure and function.

Keywords replication timing sub-nuclear compartment topologically associating domain ERCEs CTCF chromatin interactions genome architecture super-enhancer


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