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

• 成果类型: Article
• 署名作者: Kiefer, Lea; Gaudin, Simon; Rajkumar, Sandy M.; Servito, Gabrielle Isabelle F.; Langen, Jennifer; Mui, Michael H.; Nawsheen, Shayra; Canzio, Daniele
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; Ecole Normale Superieure de Lyon (ENS de LYON); University of California System; University of California San Francisco; University of California System; University of California Berkeley; Chan Zuckerberg Initiative (CZI)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8743
• DOI: 10.1126/science.adm9802
• 发表日期: 2024-07-26
• 关键词: surface recognition code; protocadherin-alpha; stochastic expression; regulatory elements; ctcf; ORGANIZATION; mouse; identification; mechanisms; generation

摘要

Expression of Protocadherin (Pcdh) genes is critical to the generation of neuron identity and wiring of the nervous system. Pcdh alpha genes are arranged in clusters and exhibit a range of expression profiles, from stochastic to deterministic. Because Pcdh alpha 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 Pcdh alpha 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.