| Cellular differentiation is a fundamental process in the construction of multi-cellular organisms. Organisms are comprised of genetically identical cells and distinct cell types originate from differential expression of the genome. The established cellular identities must be maintained through heritable changes in the transcriptional activities of individual genes. However, the mechanism underlying such epigenetic changes in gene regulation is largely unknown. Intense research in recent years has identified chromatin structures as critical determinants in the regulation of transcription. It is now believed that modulation of chromatin structures, such as reversible acetylation of histones, account for much of the heritable changes in transcriptional states; however, it is not yet clear how this is accomplished.; In Drosophila, homeotic genes are the major determinants of segmental identities. The faithful inheritance of their spatially restricted expression patterns provides an ideal system to uncover the mystery of epigenetic gene regulation. Polycomb Group (PcG) proteins function in maintaining the silent states of homeotic genes outside their normal domains. Among PcG genes, extra sex combs (esc) is unique in that it is critically required for establishment of PcG-mediated silencing during early embryogenesis, but not for subsequent maintenance throughout development. Therefore, we speculated that esc may provide a key to understanding how silencing first becomes established. We have identified an evolutionarily conserved physical interaction between ESC and another PcG protein, Enhancer of zeste (E(Z)). Their association with the histone binding protein p55 and the histone deacetylase dRPD3 directly implicates PcG silencing in the covalent modification of histones. Furthermore, dSIR2, a member of a novel class of NAD+ -dependent histone deacetylases, becomes associated with E(Z) in later stages in the absence of ESC. The developmentally regulated association of different histone deacetylases suggests the existence of distinct phases of transcriptional silencing. Finally, we have demonstrated physical associations between ESC/E(Z) complexes and various factors involved in DNA replication. Our findings unite some aspects of PcG silencing, histone modification and DNA replication, providing new insights into the epigenetic inheritance of chromatin states. |
