Mechanisms of trace amine-associated receptor gene choice

Project Summary Monoallelic expression, the preferential activation of either the maternal or paternal allele of a given gene, plays key roles in myriad biological processes including dosage compensation, cell-type specification, phenotypic variation and disease pathogenesis. Olfactory receptor genes in mammals exhibit an intriguing form of random monoallelic expression—olfactory sensory neurons in the nose choose to express a single allele of a single receptor gene from a repertoire of over 2,000 alleles. Despite significant progress in recent years, the mechanisms underlying olfactory singular expression remain unclear. Current models for how this process occurs have come from studying the large family of Odorant Receptors (ORs). The Trace Amine Associated Receptors (TAARs) constitute a much smaller receptor gene family that is also subject to monoallelic expression. However, the mechanisms underlying TAAR gene choice remains unknown. The broad goal of this project is to shed light on the core mechanisms that are required to produce olfactory monoallelic expression by identifying the commonalities and differences between TAAR and OR gene regulation. Our ongoing work has identified the specific developmental lineage of sensory neurons that preferentially choose TAAR genes, all of the genetic elements (enhancers) in the TAAR gene cluster that are required for expression, and several new transcriptional regulators that may play a role in selective TAAR expression. The Aims of the proposal are 1) to identify the functionally active sequence motifs in the TAAR enhancers that drive monoallelic expression, 2) to define how key transcription factors regulate TAAR gene choice, and 3) to determine whether and how TAAR gene expression is regulated by the three-dimensional chromatin landscape and potential interactions with OR gene enhancer networks. These experiments combine powerful genetic models and epigenetic assays to test and extend current models of mammalian monoallelic gene expression.