Zinc finger protein Wiz restricts CTCF-mediated loop extrusion to regulate clustered protocadherin genes

Researchers including Tianjie Li, Jingwei Li, Leyang Wang, and Qiang Wu have published a study in PLOS Genetics characterising how the zinc finger protein Wiz regulates the expression of clustered protocadherin (cPcdh) genes in mice.

The clustered protocadherin locus encodes a large family of cell-surface proteins critical for neuronal identity and circuit formation in the mammalian brain. Their expression is regulated through CTCF-mediated chromatin looping and cohesin-driven loop extrusion. The authors introduce COP (C2H2-ZFP Occupancy Predictor), a deep learning tool that integrates DNA sequence with protein structural features to predict genomic binding enrichment of C2H2-class zinc finger proteins.

Applying COP to the cPcdh locus, they identified Wiz among dozens of C2H2 zinc finger proteins potentially involved in CTCF-mediated regulation. Experimental validation showed that Wiz restricts loop extrusion in a genomic-distance-biased manner — effectively acting as a boundary modulator that shapes which promoter–enhancer contacts form across the locus.

The study provides mechanistic insight into how a specific zinc finger protein influences three-dimensional genome organisation and gene expression at a complex locus. It also demonstrates the utility of the COP framework for identifying previously uncharacterised regulators of chromatin architecture, which could be applied to other complex gene families.