Cohesin is required for long-range enhancer action at the Shh locus

Area of Science:

• Mammalian developmental gene regulation
• Epigenetics and 3D genome organization

Background:

• Enhancer-gene communication over large genomic distances is crucial for developmental gene regulation.
• Topologically associating domains (TADs), mediated by cohesin and CTCF, are hypothesized to facilitate long-range enhancer activity.

Purpose of the Study:

• To investigate the role of cohesin and CTCF in mediating long-range enhancer-promoter interactions for the Shh gene.
• To determine the necessity of cohesin and CTCF for enhancer activity at different genomic distances.

Main Methods:

• Utilized acute protein degradation and synthetic transcription factor recruitment in mouse embryonic stem cells.
• Perturbed cohesin and CTCF function to assess their impact on Shh gene activation by enhancers.

Main Results:

• Cohesin, but not CTCF, is required for the activation of the Shh gene by enhancers located hundreds of kilobases away.
• Cohesin is not essential for Shh gene activation by proximal enhancers or direct promoter activation.

Conclusions:

• Cohesin-mediated loop extrusion facilitates long-range enhancer-promoter communication, enabling activation of genes by distant regulatory elements.
• Cohesin's role in enhancer function is distance-dependent, being critical for distal enhancers but dispensable for proximal ones.