Gene co-regulation in the developing olfactory system
The olfactory system is a primal sensory system for most animals. The sense of smell is required in order for animals to detect food sources, avoid predators, and find mates. To accomplish this, the olfactory system must distinguish among thousands of odorants in the environment. Moreover, the olfactory system must be specialized for the niche and lifestyle of each species. Our laboratory is concerned with these two fundamental issues: How does the olfactory system distinguish odorants, and how does the olfactory system evolve individual species capabilities?
Odorant receptor regulation underlies the ability to distinguish odorants
The ability to distinguish among thousands of environmental odorants is based on a combinatorial recognition system. Encoded in the animal’s genome are about a thousand odorant receptor (OR) proteins that are expressed in the olfactory sensory neurons of the nose. Each OR protein interacts with a particular chemical structure present in an odor, and upon binding that structure, the neuron fires an action potential to communicate the presence of that chemical structure to olfactory processing centers of the brain. A critical organizing principle during development of olfactory sensory neurons is that each neuron expresses one, and only one, OR protein. Thus, each sensory neuron is tuned to detect a specific chemical structure. A given “smell” is a composition of several chemical structures; a “smell” is recognized due to the specific combination of sensory neurons that fire in response to the specific combination of chemicals present in the nose. A major part of the research in our laboratory is focused on the remarkable gene regulatory problem that underlies sensory neuronal specialization: how does each neuron express only one OR gene and silence the other ~999 OR genes present in the genome?
An epigenetic model for OR co-regulation
Based on several results in our lab and elsewhere, we are currently investigating a two-step epigenetic model: 1) all OR gene loci are “silenced” by being sequestered away from transcriptional centers of the nucleus; 2) one OR gene is “de-repressed” via a stochastic competition for a unique nuclear protein complex, thus liberating it for association with the transcriptional centers of the nucleus. Our lab is investigating the chromatin states and nuclear localizations of OR gene loci at various stages along the OSN lineage to test several predictions of this model.
OSN expression potential in development
In addition to the “one-OR-per-cell” organizing principle discussed above, the proper development and function of the olfactory system depends on spatial and temporal patterns of OSN differentiation. Presumably, developmental patterning permits proper organization of OSN subpopulations so they can properly wire to olfactory processing centers of the brain. A possible explanation for patterning is the specification of pre-cursor cells in the OSN lineage; e.g., a stem cell in a given location within the olfactory epithelium at a given time during development might be specified to produce OSNs with a restricted OR expression potential. To test this model, our lab is currently investigating the range and reproducibility of OR expression in OSN clonal subpopulations, both in vitro (i.e., cultured lines) and in vivo (i.e., isolating cell clones from developing mice). We are also investigating whether sequence (genetic) or chromatin (epigenetic) is the basis for observed restricted OR expression potential in these OSN subpopulations.
Overview of research goals
Our lab uses a wide range of genetic and cell biological techniques to investigate the molecular mechanisms that co-regulate OR genes during the development of the mammalian (mouse) olfactory system. Our research is likely to reveal novel regulatory mechanisms, since no other transcriptional regime involves so many gene components (>1000 OR genes) and gene loci (>50 chromosomal locations). The specific models we are testing should contribute to our general understanding of epigenomics – the relationships between chromatin state, nuclear organization, and gene expression – an emerging field important for development of clinical strategies in gene therapy and stem cell research, as well as for our understanding of numerous chromatin-influenced diseases (e.g., cancer).
Funding: National Institutes of Health, National Science Foundation
Current lab members: Seda Kilinc, Joyce Noble, Rutesh Vyas, Diane Meredith, Eliot Coffey, Michelle Cheng, Karley Dutra, James Farber, Brianna Parsons, Alyssa Savarino.