Chromatin structure and dynamics. polycomb silencing mechanisms, epigenetic mechanisms, developmental gene regulation, genomic programming, Drosophila genetics
The DNA sequence encodes genetic information but additional and very important layers of information are stored in the way the genetic material is organized, arranged and utilized in the nucleus. In eukaryotes, the first layer of organization is provided by the core histones around which the DNA wraps to form nucleosomes. The nucleosomes not only package the DNA but also associate with the packet a large amount of information, stored in a range of covalent modifications of the core histones. The modifications reflect the recent functional history of the particular genomic segment and influence its local availability, its structural and transcriptional properties and its interactions with the architecture of the nucleus.
We study Polycomb mechanisms, one of the major chromatin managing mechanisms in higher eukaryotes. First discovered in Drosophila as regulators of homeotic genes, they are now known to be important also in mammals for a range of phenomena from X chromosome inactivation to the regulation of cell proliferation, the maintenance of various kinds of stem cells, gene silencing, genome programming and at least some kinds of genetic imprinting. Polycomb complexes can establish and epigenetically maintain a silenced state of a chromatin domain such that the genes in that domain become transcriptionally incompetent. An alternative epigenetic mark established by a complex involving the Trithorax protein can protect genes from Polycomb silencing. The epigenetic status of a chromatin domain can be transmitted through mitosis to daughter cells and, in some cases, transmission occurs also through meiosis and inherited by the progeny of the organism.
The epigenetic marks associated with Polycomb silencing are histone deacetylation, histone H3 trimethylation at lysine 9 and lysine 27, histone H2A ubiquitylation. We do not yet understand all the roles of these modifications, although we know that the H3 methylation is read by the Polycomb chromodomain and increases the affinity of Polycomb for nucleosomes. These marks serve as a kind of memory of which chromatin domains were silenced in the previous cell cycle and should be silenced again.
In our current work, we are trying to analyse the mechanisms of recruitment of Polycomb complexes, how the component proteins interact with one another, with nucleosomes and with the transcriptional machinery. We are studying the nature of the epigenetic marks, the effects on promoters and on transcription and the interactions between Polycomb complexes and other chromatin structures such as insulators, boundary elements, telomeres, heterochromatin. We are also interested in the way in which these interactions contribute to the nuclear architecture and in the consequences for genomic programming, gene expression and cell fate.