Regulatory elements in the coding region of odorant genes March 13, 2008

Odorant receptors (ORs) constitute one of the largest gene families in mammalian genomes. Odorant receptor genes are expressed in olfactory sensory neurons (OSN), with each OSN stably expressing a single OR protein (from a single allele). How exactly this is achieved is largely unresolved (and fascinating). How do cells chose which OR is going to be expressed ? How do they make sure that only this OR is expressed (which may means that other ORs have to be repressed). In a recent Cell paper (pointed out to me by Yoav), Ryba, Belluscio and colleagues present new exciting data about the underlying mechanisms. In mouse, transgenic odorant receptor genes cannot be expressed in olfactory neurons, when directly under the control of OR promoters. The authors hypothesize that this is due to interactions between regulatory sequences in OR coding regions, and regulatory sequences in OR promoters. So they tried to eliminate this interaction by separating OR promoters from coding sequences. They placed an OR coding sequence under the control of an artificial promoter (TetO), activable by TTA. The TTA-coding gene is itself placed under the control of an OR promoter. Using this system, they managed to express the OR in a good fraction of neurons. In turn, this allowed them to observe that the expressed OR suppresses expression of endogenous ORs. Likewise, TetO-OR expression appears suppressed in neurons where an endogenous OR is expressed. The authors conclude that regulatory sequences in OR coding regions are mediating the inhibition. Identifying these sequences and what binds to them is therefore the next step … it is unclear whether sequence conservation can help, as it appears that the ~1kb OR coding sequences are highly variable.