Publication
Sima J et al. (2019) Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.

current
   October 22nd, 2019 at 4:18pm

Overview


Abstract

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.

Authors

Sima J  •  Chakraborty A  •  Dileep V  •  Michalski M  •  Klein KN  •  Holcomb NP  •  Turner JL  •  Paulsen MT  •  Rivera-Mulia JC  •  Trevilla-Garcia C  •  Bartlett DA  •  Zhao PA  •  Washburn BK  •  Nora EP  •  Kraft K  •  Mundlos S  •  Bruneau BG  •  Ljungman M  •  Fraser P  •  Ay F  •  Gilbert DM

Link

https://www.ncbi.nlm.nih.gov/pubmed/30595451


Journal

Cell

PMID:30595451

Published

February 7th, 2019