Homeotic Regulation of Olfactory Receptor Choice via NFI-dependent Heterochromatic Silencing and Genomic Compartmentalization

Expression of one out of >1000 olfactory receptor (OR) genes is stochastic but, yet, spatially organized in stereotypic anatomical segments, or “zones”, along the dorsoventral axis of the mouse olfactory epithelium. We discovered that zonal OR expression is specified by OR chromatin structure and genome architecture during olfactory neuron differentiation. Specifically, across every zone dorsally expressed ORs have higher levels of heterochromatic marks and long-range contacts than ORs expressed ventrally. However, OR heterochromatin levels and frequency of genomic contacts between ORs gradually increase towards ventral zones. Consequently, ORs from dorsal indexes accumulate high H3K9me3/H3K79me3 enrichment and become silenced in ventral zones, while ORs from ventral indexes lack activating long-range genomic interactions and, thus, cannot be chosen in dorsal segments. This process is regulated by NFIA, B, and X gradients along the dorsoventral axis, triple deletion of which causes homeotic transformations on zonal OR expression, heterochromatin formation, and genomic compartmentalization.