Abstract
Cohesin and CCCTC‐binding factor (CTCF) are key regulatory proteins of three‐dimensional (3D) genome organization. I will present direct evidence that cohesin extrudes DNA loops that are anchored by CTCF proteins in specific orientations. CTCF binding polarity controls cohesin‐mediated DNA looping. Using single‐molecule imaging of CTCF‐cohesin collisions, we demonstrate that the N‐terminus of CTCF must be oriented towards cohesin to block its ability to compact DNA. C‐terminally oriented CTCF accelerates DNA compaction by cohesin. Oriented inactive Cas9 and Cas12a ribonucleoproteins exhibit similar polar effects on DNA compaction by cohesin. RNA‐DNA hybrids (R‐loops), such as those that occur at highly transcribed genes, efficiently block cohesin‐mediated DNA compaction. Our results explain long‐standing puzzles regarding how CTCF and transcription shape the 3D genome.
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