Active regulatory elements recruit cohesin to establish cell-specific chromatin domains

As the structure of the genome is analysed at ever increasing resolution it is becoming clear that there is considerable variation in the 3D chromatin architecture across different cell types. It has been proposed that this may, in part, be due to increased recruitment of cohesin to activated cis-elements (enhancers and promoters) leading to cell-type specific loop extrusion underlying the formation of new subTADs. Here we show that cohesin correlates well with the presence of active enhancers and this varies in an allele-specific manner with the presence or absence of polymorphic enhancers which vary from one individual to another. Using the alpha globin cluster as a model, we show that when all enhancers are removed, peaks of cohesin disappear from these regions and the erythroid specific subTAD is no longer formed. Re-insertion of the major alpha globin enhancer (R2) is associated with the appearance of a new peak of cohesin at the site of insertion. In complementary experiments insertion of R2 into a “neutral” region of the genome recruits cohesin, induces transcription and creates a new large (75kb) erythroid specific domain. Together these findings support the proposal that active enhancers recruit cohesin, stimulate loop extrusion and promote the formation of cell specific subTADs. ### Competing Interest Statement J.R.H. is founder, shareholder, and paid consultant of Nucleome Therapeutics. J.R.H hold patents for Capture-C (WO2017068379A1, EP3365464B1, US10934578B2). This author declares no other financial or non-financial interests. The remaining authors declare no competing interests.