The combination of DNA with the protein complement that regulates it is known as chromatin. Depending on the degree of compaction of chromatin we can distinguish two forms of organization, Euchromatin and Heterochromatin. While Euchromatin is open and accessible, Heterochromatin is a specialized form of chromatin with a highly compacted structure. It covers regions of the genome that are highly repetitive, and by ensuring a high degree of compaction it prevents transcription as well as recombination of the repeat elements. These are very important functions because most repetitive parts of the genome are derived from transposons, selfish genetic elements capable of moving within the genome and increasing their copy number. These potentially harmful parasitic sequences must be silenced to avoid their rampant spread and the mutation and genomic instability that it can cause. The other main types of sequences coated by heterochromatin are highly repetitive arrays of elements called satellite DNA. Over the course of evolution, heterochromatic satellite regions have gained new roles in the chromosome. For example, the pericentric satellite DNA is necessary for proper chromosome segregation through its participation in centromere formation. Since repetitive DNA constitutes a large proportion of eukaryotic genomes, heterochromatin plays a key role in their function and evolution, and loss of its regulation can lead to cancer and aging-related diseases.
We study the mechanisms by which the cell recognizes repetitive and parasitic elements and compacts them into heterochromatin, and how this heterochromatic structure is maintained through mitosis. In particular, we are interested in the interaction of DNA replication and epigenetic inheritance. We have shown that repetitive regions pose impediments to the progression of the replication fork, and the DNA damage signaling and repair-like reaction that this elicits can recruit chromatin remodeling factors that deposit heterochromatic marks. In this manner, epigenetic inheritance of heterochromatin can be directly coupled to DNA replication by reestablishment of silencing marks in the wake of the replication fork. This provides an explanation to why these widely varied sequences are silenced by heterochromatin despite exhibiting no sequence conservation.
To study these phenomena, we use the small genome of the fission yeast Schizosaccharomyces pombe as a model, because it exhibits silencing mechanisms that are similar to those found in higher eukaryotes. We study the involvement if RNA interference in the formation of heterochromatin at pericentric repeats, and the role of the family of domesticated transposases CENP-B in the silencing or retrotransposons. Both pathways display interactions with the DNA replication machineries and affect the progression of the replication fork. Ultimately, we aim to discover the conserved principles that underlie epigenetic inheritance.
