Functional dissection of TADs reveals non-essential and instructive roles in regulating gene expression
2019
The genome is organized in megabase-sized three-dimensional units, called Topologically Associated Domains (TADs), that are separated by boundaries. TADs bring distant
cis-regulatory elementsinto proximity, a process dependent on the cooperative action of
cohesinand the DNA binding factor
CTCF. Surprisingly, genome-wide depletion of
CTCFhas little effect on transcription, yet
structural variationsaffecting TADs have been shown to cause gene misexpression and
congenital disease. Here, we investigate TAD function in vivo in mice by systematically editing components of TAD organization at the
Sox9/Kcnj locus. We find that TADs are formed by a redundant system of
CTCFsites requiring the removal of all major sites within the TAD and at the boundary for two neighboring TADs to fuse. TAD fusion resulted in leakage of regulatory activity from the
Sox9to the Kcnj TAD, but no major changes in gene expression. This indicates that TAD structures provide robustness and precision, but are not essential for developmental gene regulation. Gene misexpression and resulting disease phenotypes, however, were attained by re-directing regulatory activity through inversions and/or the re-positioning of boundaries. Thus, efficient re-wiring of enhancer promoter interaction and aberrant disease causing gene activation is not induced by a mere loss of insulation but requires the re-direction of contacts.
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