Eukaryotic genomes contain millions of copies of repetitive elements (RE). It is estimated that between 50 and 70% of the human genome is comprised of repeats, which include both small nucleotide stretches (tandem repeats) and transposable elements (RNA and DNA transposons). Repetitive elements are transcriptionally silenced by heterochromatin, a hallmark of which is the methylation of histone H3 at lysine 9 (H3K9me). The nematode C. elegans, has two histone methyl transferases responsible for H3K9 modification MET-2 and SET-25.
Worms lacking H3K9me show a striking increase in the transcription of all RE classes (DNA transposons, retrotransposons and tandem repeats) mainly in somatic tissues. By using ChIPseq and RNAseq to analyze the biology of worm RE’s, we identified elements that are silenced by H3K9me3 as opposed to mono- and di-methylation. Surprisingly, worms completely lacking H3K9me are viable, although they become sterile at 25°C. Their sterility correlates with a dramatic increase in DNA-damage checkpoint dependent apoptosis during oogenesis and a strong increase in repeat expression. A genome wide synthetic lethality screen demonstrated a strong dependency of worms lacking H3K9me on DNA damage response proteins for fertility. We could further show that H3K9me deficient mutants have a strong increase in spontaneous mutation rates, both when scored using a heterochromatic gene reporter, or as spontaneous genomic changes. The lesions incurred include frameshifts, translocations, insertions and deletions. We observe no detectable increase in either mitotic or meiotic chromosome missegregation, arguing that the genomic instability is not due to a potential role of H3K9me in chromosome segregation. We conclude that H3K9 methylation plays a unique and crucial role in the stabilization of repetitive DNA.
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