Miguel A. Zaratiegui-Biurrun
Epigenetic Inheritance and Genome Stability
The genomes of eukaryotes have a high abundance of repetitive DNA sequences. These sequences have accumulated through their ability to increase in number, like in the case of Transposons, which are selfish elements capable of replicating within their host genome. Repetitive sequences serve as sources of new genetic material, a major driver of evolution. However, they can also have destabilizing effects: illegitimate recombination between repeats can lead to genome rearrangements, and transposon movement can mutate genes.
Eukaryotes have evolved a method to control repetitive DNA by packaging it into tightly compacted chromatin structures called Heterochromatin. This tight packaging silences their transcription, preventing the replication of transposons, and the recombination between repeats.
We know a lot about the molecular details behind this packaging scheme: specific silencing marks decorate the nucleosomes that coat repetitive DNA, and effector proteins bind to these marks to mediate their compaction. But the way that the cell recognizes different repetitive sequences and compacts them into a common structure is very poorly understood.
In recent years we have recognized the importance of non-coding RNA and RNA interference (RNAi) in processes that localize the heterochromatin factors to repetitive DNA. We have discovered that recognition of repetitive DNA involves interactions between repetitive sequences, RNAi and the DNA replication machinery. Repetitive DNA is difficult to replicate, because it contains barriers that block the passage of the replication fork. The RNAi and heterochromatin factors react to these barriers and resolve the replication impediments, depositing the silencing signals and allowing DNA replication to continue. In the absence of these mechanisms the genome needs to engage homologous recombination to restart replication, losing the inheritance of silencing and potentially resulting in genome rearrangements.
We are using fission yeast and mammalian cells as models to investigate the mechanisms that underlie the coupling of heterochromatin function and DNA replication. We aim to discern the conserved principles behind repetitive DNA recognition and heterochromatin inheritance, and to understand their roles in the maintenance of genome stability.