CAREER: Mechanisms of Tissue-Specific Transcriptional Regulation

Goucher College, Towson MD

Investigators

Abstract

Cellular differentiation in multi-cellular organisms depends on tissue-specific gene expression. Although many genes are ubiquitously expressed, others are expressed in a restricted number of cell types or tissues at specific stages of development. Recent evidence suggests that altering the composition the core RNA polymerase II transcription machinery may regulate cell type-specific transcriptional activation. This is in contrast to the more traditional model that presumes combinations of transcriptional activator and repressor proteins regulate the time and place of transcription. The core machinery, although essential for the process of transcription, is not usually what determines the choice of promoters used during transcriptional initiation. The mechanisms that allow alternative forms of the general transcription machinery to differentially recognize specific promoters and thereby regulate tissue-specific transcription are not completely understood. The scientific program uses Drosophila germline differentiation as a model system to investigate the contributions of alternative forms of the general transcription machinery to developmentally regulated gene expression. Execution of the spermatogenesis cellular differentiation program in Drosophila depends upon transcription of a cohort of spermatid differentiation genes in germline cells. This transcriptional program requires the function of several genes including no hitter, cannonball, and meiosis I arrest, which are testis-specific homologs of TFIID subunits. Drosophila also express a testis-specific TFIIA subunit homolog. Interestingly, mammals express testis-specific homologs of TFIID and TFIIA subunits, suggesting the mechanisms regulating transcription of spermatid differentiation genes are conserved and that insights gleaned from study of Drosophila germline will contribute knowledge concerning reproductive health in humans. The educational program will incorporate undergraduates into the scientific research program. Independent laboratory research is an essential educational component for young scientists, future medical doctors and science teachers. Drosophila spermatogenesis offers a model system with genetic and molecular techniques that are relatively simple to master and yet intellectually challenging. The program will familiarize students with the scientific process and methodology valuable in a broad spectrum of life science careers, and stimulate the intellectual exhilaration that comes from independent research. An Advanced Genetics course will incorporate modern genetic analysis with traditional genetic subject matter, and the associated laboratory course will use Drosophila to demonstrate common genetic and molecular techniques that are applicable to mutational analysis in a wide range of organisms. The semester long project in the laboratory class will allow students to analyze previously uncharacterized male-sterile mutants.