Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization

By E. Nora, Anton Goloborodko, Anne-Laure Valton, J. Gibcus, Alec W Uebersohn, Nezar Abdennur, Job Dekker, Leonid A. Mirny, B. Bruneau. Cell, 2017

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Summary 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. Further, 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.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/e8afa0f77d39684b99c6679f6d08fd74cf1d90f5

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Citations in the corpus

YY1 Is a Structural Regulator of Enhancer-Promoter Loops (2017, positive): “These results were comparable to the effects observed with the rescue of CTCF-CTCF interactions in a similar experiment described recently (Figures 7F and S7C) (Nora et al., 2017), and support the model that YY1 contributes to structuring of a large fraction of enhancer-promoter loops genome-wide.”
Targeted Protein Depletion Using the Auxin‐Inducible Degron 2 (AID2) System (2021, methodology): “Since then, the original AID system has been used in many studies for observing immediate consequences after rapid depletion of proteins of interest in this system (Gibcus et al., 2018; Nora et al., 2017; Rao et al., 2017; Sybirna et al., 2020).”
Genome-wide analyses of chromatin interactions after the loss of Pol I, Pol II, and Pol III (2020, background): “predominant role in the 3D chromatin landscape, and they occupy most of the loops in mammalian cells [24-26].”
Cohesin loss eliminates all loop domains (2017, background): “Our data is consistent with a previous report that genome compartmentalization is preserved after depletion of cohesin (Seitan et al., 2013) or CTCF (Nora et al., 2017).”
Chromatin organization by an interplay of loop extrusion and compartmental segregation (2017, methodology): “Motivated by recent experiments that point toward such an interplay (12, 37), we used polymer models of chromosomes to investigate whether simultaneous action of loop extrusion and compartmental segregation can quantitatively reproduce experimental findings.”