Susan M. Gasser, Ph.D.
Director of the Friedrich Miescher Institute for Biomedical Research
Professor of Molecular Biology, University of Basel

Abstract:
Histone H3K9 methylation is a conserved modification that correlates broadly with gene repression in organisms ranging from fission yeast to man. In C. elegans, di- and tri-K9 methylation is abundant on repetitive elements (RE), including both transposons and simple repeats, and coats both pseudogenes and silent tissue-specific genes. Using a double mutant that eliminates the two C. elegans H3K9 histone methyltransferases, SET-25 and MET-2, we find that H3K9me is dispensable for development1,2, although worms become ts sterile. This correlates with extensive DNA damage-driven apoptosis in the germline, but there is no elevation in either mitotic or meiotic chromosome missegregation. Instead, we find that the loss of H3K9methylation leads to the promiscuous and widespread expression of all classes of repetitive elements (DNA and RNA transposons, and simple repeats) in both germline and somatic tissues. The loss of transcriptional silencing correlates with an accumulation of insertions and deletions at repetitive sequences, and renders worms sensitive to replication fork stalling, but not ionizing radiation. RNA-DNA hybrids accumulate in the absence of H3K9me even without exogenous stress. We conclude that a key function of H3K9me is to ensure the stability of a repeat-rich genome, most likely by suppressing the transcription of simple repeats. This is distinct from the role of H3K9me in sequestering chromatin at the nuclear envelope, which contributes to the stability of cell fate decisions,2.

1. Towbin, B.D., González-Aguilera, C., Sack, R., Gaidatzis, D., Kalck, V., Meister, P., Askjaer, P. and Gasser, S.M. (2012) Step-Wise Methylation of Histone H3K9 Positions Heterochromatin at the Nuclear Periphery. Cell 150, 934 - 947.
2. Gonzalez-Sandoval, A., Towbin, B.D., Kalck, V., Cabianca, D.S., Gaidatzis, D.,Hauer, M.H., Geng, L., Wang, L., Yang, T., Wang,. X., Zhao, K. and Gasser, S.M. (2015) Perinuclear Anchoring of H3K9-Methylated Chromatin Stabilizes Induced Cell Fate in C. elegans embryos. Cell, 163, 1333 – 1347