# A genetic screen for modifiers of cohesin clustering identifies regulators of genome folding

## TL;DR

This study uses a genetic screen to find factors that regulate cohesin clustering, which is important for 3D genome structure and folding.

## Contribution

The study identifies new regulators of cohesin activity through an imaging-based genetic screen in a sensitized background.

## Key findings

- The screen identified 7 enhancers and 10 suppressors of cohesin clustering.
- Factors in mitochondrial function and epigenetic silencing were found to regulate cohesin activity.
- Several regulators affect genome folding at multiple loci and cohesin loading.

## Abstract

The cohesin complex orchestrates 3D genome architecture through multiple steps including loading onto chromatin, DNA loop extrusion, stalling of extrusion, and unloading off chromatin. However, the upstream regulatory factors modulating these steps remain largely unexplored. Previous studies suggest that cohesin clustering correlates with its chromatin residence time and loop extrusion activity. Here, we developed, optimized, and performed an imaging-based genetic screen leveraging modulation of cohesin clustering to identify cohesin regulators. Using a sensitized background in which the cohesin unloader WAPL is partially degraded, we screened the druggable genome for effects on cohesin clustering. Through multiple rounds of screening and experimentation, we identified 7 enhancers and 10 suppressors of cohesin clustering. Several factors control genome folding at multiple loci and cohesin loading. Notably, our screen identified factors in mitochondrial function and epigenetic silencing, implicating these processes in the regulation of cohesin activity. This study offers a valuable resource identifying cohesin regulators and provides insights into upstream mechanisms governing genome folding.

A large-scale imaging study identified factors involved in protein modification and gene regulation as genome folding regulators.