Tuning cohesin trajectories enables differential readout of the Pcdhα cluster across neurons

Affiliations
  • 1Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 3Department of Biology, Ecole Normale Supérieure de Lyon, 69432 Lyon, France.
  • 4Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 5Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA.
  • 6Chan-Zuckerberg Biohub Investigator, San Francisco, San Francisco, CA 94158, USA.

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Abstract

Expression of Protocadherin (Pcdh) genes is critical to the generation of neuron identity and wiring of the nervous system. Pcdhα genes are arranged in clusters and exhibit a range of expression profiles, from stochastic to deterministic. Because Pcdhα promoters have high sequence identity and share distal enhancers, how distinct neurons choose which gene to express remains unclear. We show that the interplay between multiple enhancers, epigenetics, and genome folding orchestrates differential readouts of the locus across neurons. The probability of Pcdhα promoter choice depends on enhancer/promoter encounters catalyzed by cohesin, whose extrusion trajectories determine the likelihood that an individual promoter can “escape” heterochromatin-mediated silencing. We propose that tunable locus-specific regulatory elements and cell type-specific cohesin activity underlie the generation of cellular diversity by Pcdh genes.