Nuclear Organization and Epigenetic Regulation of Olfactory Receptor (OR) Genes

Mammalian olfaction depends on the development of specialized olfactory sensory neurons (OSNs) that each expresses one odorant receptor (OR) protein from a large family of OR genes encoded in the genome. The molecular mechanisms underlying mutually exclusive OR gene expression is poorly understood. I focused on the role of nuclear organization and epigenetic mechanisms that restrict expression to one of >1000 OR genes in developing OSNs. A current working model proposed in the field is that sequestration and silencing of OR genes within repressive chromocenters is crucial for restricting expression to only one OR gene per cell. However, my work showed that in an olfactory placode (OP) cell line derived from a founder cell whose transcriptional profile is consistent with early post-progenitor cells of olfactory epithelium OR genes are not sequestered within chromocenters but nevertheless exhibit singular OR expression. This surprising result suggests that OR sequestration might only be needed for maintenance of singularity in mature OSNs, but not as a mechanism to ensure the establishment of this singularity. Next, I investigated alternative explanations that might contribute to the establishment of singular OR transcription. Recently, we showed that LSD1, a histone lysine demethylase known to play a role in OR gene regulation, exhibits variable organization within nuclei of developing OSNs, and tends to consolidate into a single dominant compartment at the edges of chromocenters within nuclei of early post-mitotic cells of the mouse olfactory epithelium (MOE). Using the OP cell line, I show that consolidation of LSD1 appears to be cell-cycle regulated, with a peak occurrence in early G1. LSD1 co-compartmentalizes with CoREST, a protein known to collaborate with LSD1 to carry out a variety of chromatin-modifying functions. I show that LSD1 compartments co-localize with 1-3 OR loci at the exclusion of most OR genes, and commonly associate with Lhx2, a transcription factor involved in OR regulation. Together, these findings suggest that LSD1 is sequestered into a distinct nuclear space that might restrict a histone-modifying function to a narrow developmental time window and/or range of OR gene targets.