Transcriptional Repression by Histone Amino Termini in Yeast

Health Research Incorporated/New York State Department Of Health, Menands NY

Investigators

Abstract

The long term goals of this project are to understand the extent to which the histone amino termini, especially that of histone H3, contribute to transcriptional repression in vivo, and to determine the mechanisms by which they do so. Eukaryotic DNA is packaged into chromatin, and the fundamental unit of chromatin, the nucleosome, consists of about 146 base pairs of DNA wrapped around a core of histone proteins. Somewhat surprisingly, modification of the unstructured amino termini of the histones, which are not an essential structural component of the nucleosome, has turned out to be a widely used means of gene regulation. Numerous studies have implicated transcriptional regulation via modifications of the histone amino termini in diverse cellular processes, including cell cycle control, hormone response, and development. In spite of this progress, little is known of the mechanisms by which the histone amino termini influence transcriptional regulation. The principal investigator has discovered two examples in which the histone H3 amino terminus is critical for transcriptional repression in yeast. In the first example, the H3 amino terminus prevents activation by the CHA4 activator at the CHA1 promoter in the absence of inducer. In the second example, the INO1 gene is strongly derepressed in the absence of the H3 amino terminus, although little is known about the mechanism at present. The principal investigator has also found, using micorarray technology, that the H3 amino terminus exerts a broad, genome-wide repressive effect on gene expression. These findings serve as a basis to determine specific mechanisms for repression by the H3 amino terminus. In addition, experiments will be done to examine the contribution of the amino termini of histones H3 and H4 as targets in repression mediated by the histone deacetylase RPD3. DNA is the master controller and information reservoir for all of life. In non-bacterial cells, DNA is bound to histone proteins in chromatin. These proteins help the DNA fit inside the cell and participate in regulation of many processes that use DNA, including the transcription of DNA into RNA-the "readout" of the information in DNA. Studies by the principal investigator, using baker's yeast, are aimed at understanding how specific parts of the histone proteins prevent particular genes from being transcribed when they are not supposed to be. Because the basic mechanisms of transcription and components of chromatin are very similar in yeast and higher organisms, these findings will shed new light on transcriptional regulation in all non-bacterial organisms.