Project description:The genome adopts varied and specific 3D conformations in different cell types. The loop extruding factor, cohesin, is thought to play a key role in the formation of this 3D structure, however it is unknown how cell-type specificity is achieved. One proposed mechanism is that cis-regulatory elements, which are active in unique combinations in different cell types, recruit cohesin and therefore direct the formation of specific 3D conformation. We have identified genome-wide natural variation in enhancer sites in healthy human donors, by performing cohesin ChIP-seq in these cells we show that cohesin occupancy is directly correlated with enhancer activity. Identification of the genetic variants associated with the gain or loss of enhancer-like elements and associating this with the recruitment of cohesin provides evidence of a direct link between widespread genetic variation in the non-coding genome and cell-specific changes in 3D genome organization. Therefore, enhancer elements have evolved not only the ability to upregulate transcription at promoters, but also the ability to stimulate the mechanisms that insure robust interactions between them. Next, using enhancer KO models in the well characterised alpha globin locus, we show how cohesin recruitment and 3D genome organization correlates with changes in the local regulatory landscape. We then selected the strongest of the alpha globin enhancers and inserted it into a neutral region of the genome, to test if a single active enhancer was capable of recruiting cohesin and initiating the formation of a 3D chromatin domain when isolated from its native context. Our results show that an enhancer is able to direct the recruitment of cohesin when in an active state and that this is correlated with changes in the local chromatin environment, giving rise to open chromatin sites and de novo chromatin interactions in an otherwise “neutral” region of the genome. These results support the hypothesis that tissue-specific recruitment of cohesin is facilitated by enhancers and that this plays a role in establishing cell-specific changes in 3D genome conformation.

Dataset Information

Sec7 regulatory domains scaffold autoinhibited and active conformations

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Sec7 regulatory domains scaffold autoinhibited and active conformations.

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