Histone Acetylation in C. elegans Dosage Compensation

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

Females have two X chromosomes and males have one, but they all have two copies of all other chromosomes. Gene dosage, the number of copies of each gene, needs to be balanced with all other genes in the genome. Recent studies suggested that gene dosage balance is achieved in two steps. First the X chromosome is upregulated two-fold, so as to balance the single X in males to the other chromosomes which are present in two copies. However, upregulation of the two X chromosomes in females leads to excessive X chromosome expression, and one of these X chromosomes is then silenced. This process is called dosage compensation, because it compensates for imbalances caused by different numbers of X chromosomes. This project will investigate the mechanism of dosage compensation in a genetic model organism, the roundworm Caenorhabditis elegans, where animals with one X chromosome are males, and animals with two X chromosomes are hermaphrodites. The genes which function in worm dosage compensation are known, but their molecular mechanism of action needs to be elucidated. The DNA in our chromosomes is packaged into a tight structure around small proteins called histones. Turning genes on or off frequently involves addition or removal of small molecules, such as methyl or acetyl groups, from histone proteins. This project will investigate the role of the addition of an acetyl group to a specific residue, lysine 16 of histone H4. Preliminary evidence indicate that the addition of this acetyl group to histone H4 plays a role in the upregulation of the X chromosome in male worms, and removal of this acetyl group plays a role in repression of the two X chromosomes in hermaphrodite worms. The intellectual merit of this project is that it is the first detailed analysis of the role of histone modifications in worm dosage compensation and the first study of any kind addressing the mechanism of X-upregulation in worms. The results will also shed light on the general mechanism of how histone modifications can affect chromosome architecture and gene expression. Broader Impacts: The project will have a broad impact on education on several levels. First, undergraduate students will be active participants in performing the experiments and will be exposed to real life research not in a course setting. Second, a larger group of undergraduates will be exposed to the research in an upper level seminar course focusing on chromosome structure and function. To bring research into the classroom, raw data generated during the project will be analyzed by students enrolled in the course, so students can witness how data turns into publication quality images. Finally, training a postdoctoral fellow for a career which combines research and education is a central part of the project. The postdoctoral researcher will be involved in the research project during the first two years, and will be participating in discussion groups and journal clubs focused on teaching. In the final year of the project, under the mentorship of the principle investigator, the postdoctoral fellow will explore part-time teaching opportunities at the university.