Defining the components of olfactory singular expression

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Abstract Monoallelic expression is an unusual form of gene regulation that is often associated with genes that determine cell-type identity. The olfactory system exhibits an intriguing form of random monoallelic expression. Each sensory neuron in the mouse nose expresses only one out of over 2000 odorant receptor (OR) alleles. The current model for OR gene selection involves the interchromosomal aggregation of distributed enhancers into a single active super- enhancer, driven by the co-binding of transcription factors Lhx2 and Ebf. This super-enhancer complex attracts all OR promoters. How this assembly selects a single OR gene promoter for transcription is unknown. Understanding this process requires a better understanding of how OR gene promoters function in the context of this super-enhancer complex. Like OR enhancers, the promoters contain homeodomain (HD) binding sites for Lhx2 and Olf1/Ebf (O/E) binding sites for Ebf transcription factors. How these sites act in OR promoters to engage the choice mechanism is not clear. We propose a set of genetic experiments to define the role of HD and O/E sites in OR promoter function. To do this we will study targeted OR transgenes that lie outside of OR clusters, providing a unique tool to study what genetic and epigenetic features are required for OR expression. Moreover, we propose a combined genetic and biochemical approach to identify the molecular components of the OR choice mechanism in the nucleus. Taken together, these approaches seek to elucidate for the first time the molecular basis for OR monoallelic expression. Our findings will shed light on fundamental mechanisms that govern gene expression in mammals.