Genetic Mechanisms of Regulated Stochastic Gene Expression

The adaptability and robustness of the central nervous system is partially explained by the vast diversity of neuronal identities. Molecular mechanisms generating such heterogeneity have evolved through multiple independent pathways. The olfactory sensory system provides a unique and tractable platform for investigating at least two orthogonal gene expression systems that generate neuronal diversity through stochastic promoter choice: olfactory receptor genes and clustered protocadherins. Olfactory sensory neuron identity is defined by the specific olfactory receptor (OR) gene chosen. Greater than 1300 OR genes are scattered throughout the mouse genome, and expression of an OR defines a unique sensory neuron class that responds to a selective set of odorants. This work further delineated an unprecedented network interchromosomal (trans) interactions indispensable for singular OR choice. In a largely orthogonal gene expression system, I sought to understand the molecular mechanisms governing stochastic protocadherin choice. Clustered protocadherins are an evolutionary- conserved system that is involved in cell-cell identification through a series of homo- and heterophilic interactions. This work uncovered a methylation-dependent mechanism for generating stochastic gene expression in the context of cis-regulatory elements. Overall, this work highlighted divergent cis and trans transcriptional regulatory mechanisms for generating stochastic gene expression and neuronal diversity.