This project investigates the actions of two homeodomain transcription factors that help control expression of nearly all of the more than 1,000 mouse odorant receptor genes, expression so finely regulated that each olfactory nerve cell expresses just one allele of one odorant receptor gene. The overarching hypothesis for the project proposes that homeodomain transcription factor stimulation of odorant receptor gene transcription triggers local positive feedback acting through active chromatin modifications while simultaneously enhancing global negative feedback acting through repressive chromatin modifications, competing events capable of explaining the singularity of odorant receptor expression. This project tests whether the transcription factors act directly at promoters and enhancers of odorant receptor genes, and whether these events are associated with selected active chromatin modifications at odorant receptor genes.
Expression of odorant receptors, which are the largest family of mammalian genes, is so specific that each olfactory sensory nerve cell expresses only one allele of one odorant receptor gene. Mechanisms controlling gene expression are broadly interesting given their fundamental involvement in normal development, cancer and genetic susceptibility to diseases and the odorant receptors represent the most extreme and exquisite example of how cells achieve specificity of expression from a large gene family. Though poorly understood, odorant receptor gene expression does appear to depend on two homeodomain transcription factors, whose actions are the focus of this project.
|Wang, Qiang; Titlow, William B; McClintock, Declan A et al. (2017) Activity-Dependent Gene Expression in the Mammalian Olfactory Epithelium. Chem Senses 42:611-624|
|Zhang, Guangfan; Titlow, William B; Biecker, Stephanie M et al. (2016) Lhx2 Determines Odorant Receptor Expression Frequency in Mature Olfactory Sensory Neurons. eNeuro 3:|