Cohesin trajectories shape the epigenetic and transcriptional landscape of clustered Protocadherin genes for single neuron identities

Cellular individuality is often achieved by stochastic expression of single genes within tandemly-arrayed gene families. This principle is epitomized by the stochastic choice of clustered Protocadherin (Pcdh) genes which generates the extraordinary cell-surface diversity required for neural circuit assembly during development. However, the molecular mechanisms by which this diversity arises are not fully understood. Here, we show that stochastic Pcdh gene choice requires “escape” from silent heterochromatin by a distal transcriptional enhancer. These enhancer/promoter encounters, that lead to promoter derepression, are catalyzed by cohesin, whose processivity, density and stalling at boundaries define the probability of choice of Pcdh genes by determining the probability of enhancer/promoter contacts in mouse olfactory sensory and cortical neurons. We propose that coupling between an epigenetic switch and the modularity of cohesin trajectories allows for different Pcdh profiles to arise across neuronal cell-types, underlying the diversities of their morphologies and functions in the nervous system. More broadly these principles add a layer of regulatory finesse for the generation of transcription diversity from genes arranged in clusters.