CRISPR epi-editing reveals regulatory crosstalk between alternative promoters and splicing in Neurexin isoform expression

The use of alternative promoters and splicing increases molecular complexity and diversifies cellular functions. However, mechanisms of crosstalk between transcription and splicing remain poorly understood. Here, we utilize CRISPR epi-editing in neurons to manipulate isoforms of the synaptic organizer, Neurexin-1, and elucidate mechanisms underlying the co-regulation of alternative promoters and splicing. Surprisingly, silencing individual Neurexin-1 promoters altered downstream promoter activity via transcriptional interference and biased splicing decisions. Our data reveals transcriptional interference as key to shaping cell type-specific Neurexin-1 isoforms in the mouse hippocampus and demonstrates the power of epi-editing to uncover regulatory interactions between RNA processes in the brain.