The role of cohesin and DNA loop extrusion in the generation of single neuron identity

Stochastic and combinatorial expression of clustered Protocadherin (Pcdh) genes generates extraordinary cell-surface protein diversity, which provides individual neurons with a unique cell surface 'barcode' that functions in neuronal self/non-self discrimination. Recent advances in understanding the mechanisms by which individual neurons randomly express Pcdh genes have revealed critical insights into the function of the cohesin complex, its unloader WAPL, and the insulator protein CTCF in neural self/non-self discrimination. The unique genomic architecture of the Pcdh locus - where nearly 60 tandemly organized promoters compete for a handful of shared enhancers over nearly 1 million base pairs of DNA - have provided novel insights into how enhancers and promoters communicate, and how these interactions vary with genomic distances and between distinct cell-types. These studies highlight the importance of investigating cohesin and its DNA loop extrusion activity in mice, where the relative stoichiometries of the cohesin complex and its regulators, and thus their activities, differ among neural cell-types, and where molecular mechanisms can be directly linked to cellular physiology and brain development. Here, we review recent findings and discuss how the Pcdh gene cluster has become a new paradigm for the study of the molecular functions of cohesin, its role in the regulation of gene expression, and the implications regarding neuropsychiatric and neurodevelopmental diseases.