The essential role of histone H3K9 methylation in stabilizing the genome — ASN Events

The essential role of histone H3K9 methylation in stabilizing the genome (#55)

Susan Gasser 1 , Jan Padeken 1 , Veronique Kalck 1
  1. Friedrich Miescher Institute for Biomedical Research, Basel, BASEL, Switzerland

The methylation of lysine 9 of histone 3 (H3K9me) constitutes a major histone modification and a hallmark of constitutive heterochromatin. Lysine can be mono-, di- or tri-methylated, which provides a binding site for me-lysine readers like HP1, that in turn compact and silence heterochromatic domains. In C. elegans an additional Chromodomain containing “reader” of H3K9 methylation, CEC-4, serves to anchor chromatin at the nuclear envelope, independent of the chromatin’s silent state. In C. elegans, H3K9me is enriched on silent tissue-specific genes, pseudogenes and repetitive elements. Using a double mutant in the two H3K9 methytransferases, MET-2 and SET-25, we found that all detectable H3K9me is lost. Nonetheless, H3K9me-deficient worm embryos support proper cell division and whole worm differentiation. We find, however, that adults lacking H3K9me are infertile due to DNA damage-driven apoptosis in the germline. This is enhanced in a temperature-dependent manner. These worms are also sensitive to dNTP depletion, paused replication forks and replication stress. RNA sequencing reveals the widespread expression of transposons and simple repeat elements in both germline and somatic tissues, upon loss of H3K9me. This triggers the formation of RNA:DNA hybrids particularly over transcribed repetitive elements. Concommitantly, we find a dramatic accumulation of insertion and deletion mutations in germline and somatic chromosomes.
Intriguingly, the loss of MET-2, which reduces H3K9me1, me2, and me3 to 20% of wild-type levels, provokes the same R-loops and delocalizes chromosome arms from the nuclear periphery, leading to sterility and synthetic lethality with a variety of RNA processing enzymes and factors involved in DNA repair. In particular, the human tumor suppressor BRCA1 interacting factor is synthetic lethal with loss of H3K9 methyl-mediated repression of repeats. This is not the case in the set-25 mutant, which loses H3K9me3, but retains H2K9me2. This clearly distinguishes the physiological roles of di- and tri-methylated H3K9 and links genome stability with the repression of repetitive elements.

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