Apr 21
Biology Seminar: Kevin Monahan, "The Epigenetic Basis of our Sense of Smell"
Vertebrates smell by using G-protein coupled odorant receptor proteins (ORs) on olfactory sensory neurons (OSNs) to detect chemicals present in the environment. The mouse genome encodes over 1,400 genes for ORs, but olfactory sensory neurons obey a “one receptor per neuron” rule, such that each neuron expresses only one allele of one of these OR genes. This gene choice is controlled epigenetically. In each neuron, the single transcribed OR allele localizes to an active chromatin hub in the nucleus where it associates with regulatory enhancer elements, whereas the hundreds of inactive OR genes are sequestered in transcriptionally silent heterochromatin. However, it remains unknown how each neuron selects a single OR allele for expression in the first place. Here, we show that OR choice is coordinated through opposing activating and repressing mechanisms that act in immature neurons. We demonstrate that transcription factors Lhx2 and Ldb1 bind to hundreds of sites near OR genes in immature OSNs. At the same time, immature OSNs express a transcriptional repressor, testis expressed gene 15 (Tex15), that helps target heterochromatin to OR gene clusters. Tex15 knock out (KO) mice exhibit a dramatic skewing of OR gene choice. In particular, a few OR genes get selected at a very high rate, whereas many other OR genes are no longer expressed. Strikingly, the OR genes that are overexpressed in Tex15 KO mice are located close to Lhx2 and Ldb1 binding sites. We show that these genes have increased expression in immature neurons of Tex15 KO mice, and go on to preferentially associate with the active enhancer hub. Taken together, these findings suggest a central role for OR transcription in driving the assembly of enhancer hubs and demonstrate the importance of transcriptional repression of early OR expression for ensuring the generation of a diverse population of olfactory sensory.
from Biology