Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.

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

Source：Cell, 2018.

DOI：10.1016/j.cell.2018.11.036

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

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.

• Institution
  university of michigan; university of california