Molecular mechanisms of chromosome repression and dosage compensation in C. elegans

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

Investigators

Abstract

Molecular mechanisms of chromosome repression and dosage compensation in C. elegans The phenomenon of "dosage compensation" in animals is a chromosome-wide process that equalizes the expression of X chromosomes in the different sexes. This project will investigate how the positions and structure of X chromosomes in the nucleus influences how genes are repressed in the model organism, C. elegans. The research will be performed by graduate and undergraduate students, who will be trained in research methods, data analysis, and scientific writing in preparation for future careers in science. In addition, the Principle Investigator and students will partner with the University of Michigan Museum of Natural History to be trained as Science Communication Fellows. They will then share research results and insights with museum visitors through Scientist Spotlight activities and Investigate Lab Public Programs. The Principle Investigator will also participate in museum-led outreach activities for underserved middle school students through the Science for Tomorrow Program, and for lay adult audiences through the Science Cafe Program. The Principle Investigator and students will also arrange more informal scientific outreach visits to local K-12 schools. The project will investigate the impact of chromosome structure and organization on development by studying the model system of dosage compensation in the nematode C. elegans. In this organism, a complex resembling the mitotic chromosome condensation machinery binds both X chromosomes of XX hermaphrodite to downregulate gene expression two-fold and bring gene expression levels to that seen in XO males. During this process, the X chromosomes are compacted and tethered to the nuclear lamina to stabilize repression of genes. How this nuclear reorganization takes place is not understood at the molecular level. The project will investigate the contribution of a nuclear lamina-localized protein, CEC-4, by investigating its chromosomal localization patterns, determining its binding partners, and analyzing the contributions of each to chromosome and nuclear organization. The project will also investigate the contribution of the nuclear hormone receptor SEX-1. Genetic evidence indicates that SEX-1 mutations partially disrupt dosage compensation making the process more sensitive to further disruptions. The project will identify the chromosomal targets of SEX-1, and will determine how these targets contribute to dosage compensation and how SEX-1 and CEC-4 cooperate in these processes. The research will involve the use gene editing technologies to generate tagged proteins and mutant versions, genomics to obtain a high-resolution map of chromosomal association patterns and gene expression effects, and superresolution microscopy to analyze the effects on chromosome structure and nuclear organization. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.