Targeting the X for Chromosome-Wide Gene Regulation.

Abstract

Dosage compensation is an essential gene regulation mechanism that balances X-linked gene expression in organisms that utilize a chromosome-based sex determination strategy. The mechanisms of dosage compensation that have been studied all involve specialized gene regulatory machineries that specifically localize to and function on the dosage compensated chromosome(s). In C. elegans, this machinery is called the Dosage Compensation Complex (DCC) and it balances X linked gene expression between XX hermaphrodites and XO males by binding the two hermaphrodite X chromosomes to reduce expression two-fold. The goal of my thesis is to address the gap in our understanding of how the initial targeting of the DCC to the X chromosomes is achieved. In this work I have examined the requirements within a sub-complex of the DCC, Condensin IDC, for X chromosome localization and contributed to our understanding of Condensin I localization in mitosis and meiosis. I have also provided the first evidence that chromatin, specifically the histone variant H2A.Z/HTZ-1 contributes to DCC targeting. Finally, I have demonstrated that the DCC regulatory subunit, DPY-30, functions in dosage compensation in a manner that is completely independent of its role in H3K4 methyltransferase complexes. Together, this work serves as the first investigation on the role of chromatin in targeting the DCC to the X chromosomes in C. elegans and serves as an example of how chromatin organization functions in eukaryotic gene regulation.