Distal regulatory elements (DREs), such as enhancers, can regulate genes across megabase-long distances, presumably via coming into close spatial proximity. The establishment of new transcriptional programmes during cell type transitions is associated with widespread rewiring of the spatial organisation of the genome, including gain and loss of chromatin interactions. Extensive effort has been invested into understanding how chromatin interactions are formed during development, yet the mechanisms underlying their developmental loss remain largely unclear. By leveraging chromatin accessibility-assisted footprinting, acute protein degradation and chromatin conformation capture, we show that loss of promoter interactions cannot be explained by reduced binding of sequence-specific transcription factors (TFs). Instead, we identify a subset of interactions that depend on cohesin for programmed developmental disruption. These sites are characterized by high Polycomb enrichment and TF occupancy and engage in strong long-range interactions that undergo extensive differentiation-dependent rewiring. Preventing interaction loss by acute cohesin degradation results in the preferential downregulation of associated genes. Together, these results suggest that cohesin indirectly regulates developmental loss of Polycomb interactions by enabling the acquisition of other potentially regulatory contacts in a process that may shape transcriptional programs during cell type transitions. ### Competing Interest Statement The authors have declared no competing interest. European Research Council Helmholtz Society, VH-NG-1604

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An analytical pipeline called Iteratively Defined Lengths of Inaccessibility (IDLI) maps the genome-wide occupancy of a range of nucleosome types and shows that most nucleosomes exhibit programmed ‘di...

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A biweekly scientific journal publishing high-quality research in molecular biology and genetics, cancer biology, biochemistry, and related fields

Background The ability to deposit histone H3K27-trimethyl (me3) marks is essential for transcriptional repression by Polycomb Repressive Complex 2 (PRC2). This is largely attributed to Polycomb repres...