Genome rearrangements are rare and sporadic events that can lead to cancer in humans. Yet, genome rearrangements are developmentally regulated in diverse organisms, leading to the programmed elimination of a fraction of the germline genome during somatic differentiation. In the unicellular eukaryote Paramecium, massive, reproducible and inducible DNA elimination events occur at each sexual cycle, during the development of the somatic nucleus. This organism provides thus an excellent model system to study the fundamental mechanisms controlling genome dynamics in eukaryotes.
In this organism, the eliminated sequences include transposable elements (TEs) as well as tens of thousands of unique intervening sequences derived from TEs. No conserved sequence motif that might serve as a specific recognition signal was identified among eliminated sequences. Understanding how such diverse sequences are recognized and excised remains challenging.
The process involves small (s)RNA-directed heterochromatin formation and subsequent DNA excision and repair. sRNAs are produced from the germline genome during meiosis and guide the deposition of histone H3 post-translational modifications (H3K9me3 and H3K27me3) onto sequences to be eliminated in the developing somatic nucleus, and specifically tether the DNA cleavage and repair machinery.
We demonstrated that the Paramecium histone methyltransferase Ezl1, a homolog of the mammalian PRC2 catalytic subunit, catalyzes H3K27me3 and H3K9me3 on TEs. We currently investigate how the Ezl1 protein is recruited to TEs, and how the histone H3 post-translational modifications trigger DNA cleavage and repair. We combine a large panel of molecular, cellular, genetic and biochemical approaches to study the role of chromatin factors in the control of DNA elimination.