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Cell. 2017 May 18;169(5):930-944.e22. doi: 10.1016/j.cell.2017.05.004.

Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.

Author information

1
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA. Electronic address: elphege.nora@gladstone.ucsf.edu.
2
Institute for Medical Engineering and Science and Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Howard Hughes Medical Institute, Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.
4
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
5
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94143, USA; Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA. Electronic address: benoit.bruneau@gladstone.ucsf.edu.

Abstract

The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Furthermore, our data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding, these results provide new fundamental insights into the rules governing mammalian genome organization.

PMID:
28525758
PMCID:
PMC5538188
DOI:
10.1016/j.cell.2017.05.004
[Indexed for MEDLINE]
Free PMC Article

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