The role of facultative heterochromatin in transcriptional regulation of olfactory sensory neurons

Abstract

Olfactory receptors (ORs) are expressed by olfactory sensory neurons (OSNs) and are crucial for animal survival because they are responsible for the detection of different odorants in the environment. ORs are members of one of the largest gene family in mammals, are encoded by hundreds of alleles, and display monogenic and monoallelic expression in OSNs. In the olfactory epithelium (OE), these alleles are not randomly transcribed. They are expressed in OSNs spatially constrained to specific zones in the OE. This pattern of expression can already be distinguished at the embryonic OE. Mechanisms involved in ORs' zonal expression remain elusive. OSNs have a peculiar nuclear architecture in which the facultative heterochromatin, enriched in H3K27me3, is frequently concentrated around a central block of constitutive heterochromatin. The two alleles of each OR gene seem to be segregated in these two different heterochromatin compartments, forming clusters. This specific nuclear architecture is responsible for the repression of hundreds of ORs alleles in each OSN. The differential silencing by facultative or constitutive heterochromatin could be involved with OR expression in different zones in the OE. The role of facultative heterochromatin in OSN gene expression has not been elucidated. A prominent heterochromatin block is also present during chromosome X inactivation, and LINE-1 transposons are involved in this block formation in murine stem cells. In these cells the transcription of some of these transposons is important for chromosome silencing, which relies on the Polycomb Repressor Complex 2 (PCR2). The OR loci are enriched in LINE-1 transposons. Our hypothesis is that LINE-1 in proximity to OR genes are involved in these loci distribution in OSN nucleus and in the formation of the heterochromatin domain, which would result in OR gene silencing. To understand the role of facultative heterochromatin in OSN gene expression this project aims to: (1) describe the distribution of H3K27me3 and PRC2 proteins in OSNs nuclei during OE development; (2) investigate OR gene interaction with H3K27me3 in mature OSNs from different OE zones; (3) describe LINE-1 distribution in OSNs nuclei and; (4) investigate the transcription of these transposons by different OE cells. The results of this project will be important to elucidate the role of facultative heterochromatin in OR gene repression in different OE zones and the role of transposons in heterochromatin organization in the OSN nucleus. (AU)