Developmentally programmed loss of long-range Polycomb interactions is regulated by cohesin

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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Noncoding transcription controls the developmental dynamics of long-range gene regulation

The genomic regions regulating gene expression are often themselves transcribed into a variety of noncoding RNAs (ncRNAs). However, the regulatory roles of this noncoding transcription remain largely ...

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Mechanisms and functional implications of long-range enhancer-dependent gene regulation - Nature Genetics

Development depends on gene regulation by enhancers across long genomic distances. This Perspective discusses mechanisms enabling long-range enhancer–promoter communication and the potential advantage...

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Enhancer control of promoter activity and variability via frequency modulation of clustered transcriptional bursts - Nature Genetics

Tünnermann et al. use live-cell imaging to study promoter activity under the control of an enhancer inserted at different genomic distances. RNA production from the promoter occurs in clusters of tran...

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Mechanisms underlying disease-causing variants in promoters and enhancers - Nature Genetics

This Review discusses how rare-disease-causing variants in the noncoding genome impact gene regulation, why these examples are so few and how new approaches could accelerate discovery of noncoding var...

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X-chromosome inactivation draws L1 mutagenesis to the human X chromosome

X-chromosome inactivation (XCI) enables gene dosage compensation in XX eutherians. Long interspersed element-1 (LINE-1 or L1) retrotransposons are unusually abundant on the human X chromosome and are ...

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