FRIBIO-Biologi og biomedisin

Correct differential gene expression is essential for proper development of tissues and organs. While the initial patterns of gene expression are established by classical transcription factors, the maintenance of correct gene expression relies on epigenet ic mechanisms, one of which relies on differential modification of the N-terminal tails of the nucleosomal histones (e.g. acetylation and methylation of lysines). The chromatin of genes that are active and silenced display distinct patterns of histone mod ifications. As these modification patterns can be propagated through many cell divisions, they can serve as a medium for marking which genes are active and which are not. While many of the enzymes that set and erase these marks have been well studied, muc h less is known of how the histone modifications are recognised and used. Bromo domains and chromo domains are two small protein modules that bind to acetylated and methylates lysines on histones, respectively. They are found in many epigenetic regulators , often together with a third domain, the PHD finger. We have shown that it can cooperate with an adjacent bromo domain in binding to nucleosomes in vitro. Little is known, however, about their functions at the process level. In this project the function of adjacent bromo domains and PHD fingers will be studied in two model proteins involved in epigenetic gene regulation in Drosophila, the trithorax group protein Ash1 and the transcriptional cofactor CBP. The consequences of loss and replacement of the tw o domains will be investigated in cell culture with endogenous and artificial reporters as well as in transgenic flies. There are about 100 human PHD finger proteins and more than 40 bromo domain proteins, 20 of which carry both domains. We expect that th e knowledge gained from studying the two model proteins in this project may be extended to better understand the function of this larger protein family and their role in differential gene expression.