Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization
Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology
Biochemistry, Biophysics, and Structural Biology | Computational Biology | Systems Biology
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.
DOI of Published Version
Cell. 2017 May 18;169(5):930-944.e22. doi: 10.1016/j.cell.2017.05.004. Link to article on publisher's site
Nora, Elphege P.; Goloborodko, Anton; Valton, Anne-Laure; Gibcus, Johan H.; Uebersohn, Alec; Abdennur, Nezar; Dekker, Job; Mirny, Leonid A.; and Bruneau, Benoit G., "Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization" (2017). Program in Systems Biology Publications and Presentations. 111.