Analysis of Chromatin Modification and Remodeling in the Transcriptional Regulation of the Wnt/Wg Pathway.

Abstract

The Wnt/Wingless pathway regulates many developmental events and is conserved throughout the animal kingdom. Disruption of the Wnt/Wingless pathway has been linked with many diseases. Due to its importance, how Wnt/Wingless signals to influence animal development has been intensively studied. Although many nuclear proteins have been implicated to regulate Wnt/Wingless transcription, some of which are chromatin remodelers, direct evidence for chromatin alteration of Wnt/Wingless target genes is largely lacking. In this thesis, I will discuss the roles of both ATP-dependant chromatin remodeling and histone covalent modification in transcriptional regulation by Wingless (Wg, the fly Wnt). Chapter I is a general introduction to our current knowledge of the Wnt/Wg signaling pathway and chromatin remodeling. In chapter II, evidence for the Wg induction of widespread histone acetylation is presented. In contrast to many other studies which found histone acetylation at distinct loci, we found widespread histone acetylation induced by Wg signaling at two Wg target regions that was independent of transcription. Possible histone acetyltransferases required for histone acetylation is be discussed. In chapter III, I present my work on how Polycomb group proteins and H3K27 methylation negatively regulate transcription of Wg target genes. High levels of H3K27me3 at Wg targets are regulated by the histone methyltransferase Enhancer of Zeste (E(z)), a Polycomb group protein; E(z) is required for repression of Wg targets. However, Wg activation does not necessarily remove H3K27me3, and the implication of this phenomenon is discussed. In chapter IV, I discuss dual roles for the ATP-dependent chromatin remodeler Brm complexes in Wg transcriptional regulation. Brm complexes are required to repress some Wg targets in the absence of Wg signaling; whereas, other targets require Brm complexes to be fully activated by Wg. The directness of the regulation is discussed.