TY - JOUR T1 - Antisense lncRNA transcription drives stochastic Protocadherin α promoter choice JF - bioRxiv DO - 10.1101/360206 SP - 360206 AU - Daniele Canzio AU - Chiamaka L. Nwakeze AU - Adan Horta AU - Sandy M. Rajkumar AU - Eliot L. Coffey AU - Erin E. Duffy AU - Rachel Duffié AU - Matthew D. Simon AU - Stavros Lomvardas AU - Tom Maniatis Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/07/01/360206.abstract N2 - Stochastic and combinatorial activation of clustered Protocadherin (Pcdh) α, β, and γ gene promoters generates a cell-surface identity code in individual neurons that functions in neural circuit assembly. Here we show that Pcdhα promoter choice requires transcription of a long noncoding RNA (lncRNA) initiated from newly identified promoters located in the protein coding sequence of each Pcdhα exon. Antisense transcription of the lncRNA through the sense promoter results in its activation and in DNA demethylation of the binding sites for the CCCTC-binding protein, CTCF, located in close proximity to both sense and antisense promoters. Increased CTCF binding promotes the assembly of long-range DNA contacts between the activated promoter and a neuron-specific enhancer, thus locking in the epigenetic state of the stochastically chosen Pcdhα promoter. Examination of this hierarchical molecular mechanism in differentiating olfactory sensory neurons, suggests that antisense Pcdhα transcription is a key prerequisite for stochastic Pcdhα promoter choice in vivo. ER -