Date of Degree

6-2020

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Paul Feinstein

Committee Members

Diana Bratu

Carmen Melendez-Vasquez

Mark Emerson

Thomas Bozza

Subject Categories

Cell Biology | Developmental Biology | Genetics | Molecular Biology

Keywords

singularity, odorant, TetO, competition, olfaction, transcription

Abstract

Singular gene expression is a common phenomenon in biology, making its appearance in immunoglobulin selection, protocadherin expression, X chromosome-inactivation, random monoallelic expression, and olfactory receptor choice. Singularity involves an activation and a feedback step. The mechanisms of singular gene choice have some capacity to integrate additional member genes while still maintaining singularity, but will activate an additional member if an earlier choice was incapable of triggering the feedback step. Odorant Receptor (OR) genes are substantially divergent from each other in terms of coding sequence, promoter structure, and genomic locus, all of which plays a role in how many Olfactory Sensory Neurons (OSNs) express a specific OR gene in singularity. The number of OSNs that express a specific OR gene, referred to as “representation” in this thesis, was previously enhanced through the five prime addition of a multimerized homeodomain enhancer sequence derived from OR enhancers. These "High Representation" (HR) OR transgenes maintain the properties of singularity, but the use of the exogenous tTA/TetO expression system to generate singular OR expression in OSNs suggests that singularity is not unique to OR promoters and enhancers. The intersection of HR and tTA/TetO transgenes reveals a competitive hierarchy in the OSN nucleus, in which the order of activation dictates the hierarchal relationship between HR transgenes and TetO transgenes. The capacity for HR transgenes to limit TetO activity even when replacing the OR coding sequence of either transgene with a marker coding sequence suggests a more generalized mechanism to explain how OSNs and other systems generate singularity.

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