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The role of Tex15 in shaping stochastic olfactory receptor gene choice.

Tex15 在塑造随机嗅觉受体基因选择中的作用。

基本信息

批准号：
10826734
负责人：
Nusrath Yusuf
金额：
$ 3.91万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10826734
关键词：
Adolescent Alleles Binding Binding Proteins Biochemical ChIP-seq Chemicals Chromatin Chromatin Structure Complex DNA Methylation DNA Transposable Elements DNA methylation profiling Data Deposition Detection Development Down-Regulation Elements Ensure Environment Epigenetic Process Excision Faculty Fellowship Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Genomics Heterochromatin Histones KDM1A gene Knock-out Knockout Mice Mammals Maps Mediating Mentorship Methylation Molecular Mus Mutant Strains Mice Nervous System Neuronal Differentiation Nuclear Odorant Receptors Olfaction Disorders Olfactory Epithelium Pattern Perception Phenotype Process Proteins Receptor Gene Regulator Genes Repression Rest Role Sensory Shapes Smell Perception Specificity Spermatocytes Students Techniques Testing Testis Training Transcriptional Silencer Elements Up-Regulation Work chemical binding computational neuroscience experimental study gene repression genome-wide histone demethylase histone methyltransferase innovation insight link protein methylation pattern mutant nerve stem cell novel olfactory receptor olfactory sensory neurons piRNA programs promoter receptor expression recruit single-cell RNA sequencing transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT The incredible specificity with which we can discern a vast diversity of smells emerges from how olfactory sensory neurons (OSN) express olfactory receptor (OR) genes. These OR genes encode the proteins that bind chemical odorants. Each OSN stochastically transcribes only one allele of an OR gene. An OSN can choose to express any one of the approximately 1400 OR genes or 2800 alleles. There is no one to one relationship between an odorant and an OR as a combination of ORs are involved in the detection of one odorant. Thus, the diversity of ORs expressed is important to the main olfactory epithelium’s (MOE) ability to detect a vast range of smells. The choice of an OR gene occurs as OSN progenitors mature into an OSN. Recent work has revealed remarkable remodeling of the local chromatin and co-expression of multiple OR genes during this period, but the molecular mechanisms governing these processes and their connection to a singular OR allele expression in a mature OSN remain unknown. We show that testis expressed 15 (Tex15), a protein that has only been studied in the testes where it regulates methylation and silencing of transposons, is crucial for stochastic OR gene choice. We find that when Tex15 is knocked out there is a dramatic reduction in the diversity of expressed OR genes with a few OR genes dominating stochastic choice. Strikingly, Tex15 is only transiently expressed in OSN progenitors during a period of OR co-expression. Our central hypothesis is that Tex15 is epigenetically controlling stochastic OR gene choice, either by regulating DNA methylation or other aspects of OR gene chromatin structure. Aim 1 will determine whether Tex15 is required for transient co-expression of multiple OR genes in OSN progenitors. In aim 2, we will determine whether Tex15 protein binds to OR genes. Finally in aim 3, our experiments on primary OSNs from Tex15 null mice will determine how gene repression is mediated in OSN progenitors – through methylation or deposition of repressive heterochromatin. Together, these experiments will elucidate a novel aspect of how OSNs come to stochastically choose a single OR and how Tex15 gene and protein guides this specific yet diverse choice. We anticipate this project will uncover new and/or unexpected role for Tex15 in the MOE. This will also reveal the key molecular underpinnings for how our sense of smell develops and may provide important insight to further understand the mechanisms of smell disorder. The proposed fellowship will train this applicant in several innovative techniques in biochemical, cellular, molecular, and computational neuroscience. The established faculty-student mentorships will ensure proper scientific and professional training necessary to become a successful, independent sensory and computational neurobiologist.

项目总结/文摘