TEX15 safeguards neuronal diversity in the mouse olfactory system

Animal chemosensory systems discriminate between complex mixtures of chemical compounds by leveraging large repertoires of chemoreceptor proteins. To organize information from many receptors, these systems often employ a one-receptor-type per cell organization (Fulton et al. 2024). This structure requires a gene regulatory mechanism that can coordinate the generation of many distinct types of sensory neurons, each expressing a different receptor (Yusuf and Monahan 2024; Danoff et al. 2025; Pourmorady and Lomvardas 2022; Bashkirova and Lomvardas 2019; Monahan and Lomvardas 2015; Brann and Datta 2020). Here we show that testis-expressed gene 15 (Tex15) is a critical component in an epigenetic mechanism that safeguards diverse olfactory receptor (OR) choice in the mouse olfactory system. Tex15 is required to inhibit an initial wave of olfactory receptor gene transcription that occurs as olfactory sensory neuron progenitors differentiate. In Tex15 knockout (Tex15-/-) mice, this repression fails: the early-transcribed OR genes get expressed at abnormally high levels, get chosen at high rates, and come to dominate the neuronal population. This results in a profound reduction in the diversity of OR gene choice and disrupted spatial patterning of the olfactory epithelium, while maintaining the expression of one receptor per cell. These changes in OR gene expression are accompanied by reduced deposition of H3K9me3 heterochromatin on OR genes and the preferential formation of interchromosomal enhancer hubs around the dominant ORs. We propose that Tex15 directs a heterochromatin-based transcriptional repression mechanism that counter-balances early OR transcription, thereby preventing the heterogeneous onset of OR transcription from skewing OR choice.