Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains
from Genomic Compartmentalization
#MMPMID28525758
Nora EP
; Goloborodko A
; Valton AL
; Gibcus JH
; Uebersohn A
; Abdennur N
; Dekker J
; Mirny LA
; Bruneau BG
Cell
2017[May]; 169
(5
): 930-944.e22
PMID28525758
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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.
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