AN INVESTIGATION IN THE CROSS REGULATION BETWEEN HISTONE H3 METHYLTRANSFERASES AND DEMETHYLASES IN SCHIZOSACCHAROMYCES POMBE

Abstract

In this thesis, I investigated the crucial cross-regulation among the histone H3 methyltransferases Set1 (H3K4) and Clr4 (H3K9), and the lysine-specific demethylases Lsd1/2 in the fission yeast Schizosaccharomyces pombe. My results demonstrate a complex, antagonistic regulatory circuit essential for maintaining the histone methylation landscape and controlling gene expression patterns. I revealed that the protein levels of Lsd1/2 are oppositely regulated by Set1 and Clr4, a process that is controlled by the ubiquitin-proteasome system (UPS). Specifically, the catalytic function of Set1 is shown to be essential for stabilizing Lsd1/2 proteins, suggesting a mechanism in which Set1 protects them from degradation by the Clr4 complex (CLRC), potentially by methylating specific lysine residues that compete with ubiquitination. Furthermore, this regulation is critical for the cellular adaptive response, as Set1-dependent upregulation of Lsd1/2 proteins is crucial for regulating gene expression under heat stress.