An epigenetic repressor TRIM66 dictates monogenic olfactory receptor expression, neural activity, and olfactory behavior.

Olfactory receptor gene choice is an intricate example of monogenic and monoallelic expression, where one out of over 1000 receptor genes is transcribed in each olfactory sensory neuron. This process involves expression of multiple olfactory receptor genes in immature neurons, followed by silencing of all but one receptor genes during maturation. However, the molecular identity of the repressors remains mysterious. Here, we discover TRIM66 as a key repressor. Multiple receptor genes are retained at low levels in most single mature OSNs after deletion of Trim66, leading to decreased expression of the vast majority of olfactory receptor genes. Mechanistically, TRIM66 can bind to, assembly, and repress olfactory receptor enhancers, thereby silencing extra olfactory receptor genes. Functionally, deletion of Trim66 leads to severe defects in the olfactory information processing and innate olfactory behaviors. Our study provides the missing link in understanding the transition from polygenic to monogenic olfactory receptor expression.