Journal
CELL
Volume 162, Issue 4, Pages 900-910Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.07.038
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Funding
- MOST [2009CB918700, 2012CB316503]
- NSFC [31171015, 31470820, 81261120390, 91019016]
- Shanghai Municipality [13XD1402000, 14JC1403600]
- State Key Laboratory of Medical Genomics
- NIH [NS043915, HG001696]
- NCI [3P01-CA013106-41S1]
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CTCF and the associated cohesin complex play a central role in insulator function and higher-order chromatin organization of mammalian genomes. Recent studies identified a correlation between the orientation of CTCF-binding sites (CBSs) and chromatin loops. To test the functional significance of this observation, we combined CRISPR/Cas9-based genomic-DNA-fragment editing with chromosome-conformation-capture experiments to show that the location and relative orientations of CBSs determine the specificity of long-range chromatin looping in mammalian genomes, using protocadherin (Pcdh) and beta-globin as model genes. Inversion of CBS elements within the Pcdh enhancer reconfigures the topology of chromatin loops between the distal enhancer and target promoters and alters gene-expression patterns. Thus, although enhancers can function in an orientation-independent manner in reporter assays, in the native chromosome context, the orientation of at least some enhancers carrying CBSs can determine both the architecture of topological chromatin domains and enhancer/promoter specificity. These findings reveal how 3D chromosome architecture can be encoded by linear genome sequences.
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