Impact of nucleic acid and methylated H3K9 binding activities of Suv39h1 on its heterochromatin assembly

SUV39H is the major histone H3 lysine 9 (H3K9)-specific methyltransferase that targets pericentric regions and is crucial for assembling silent heterochromatin. SUV39H recognizes trimethylated H3K9 (H3K9me3) via its chromodomain (CD), and enriched H3K9me3 allows SUV39H to target specific chromosomal regions. However, the detailed targeting mechanisms, especially for naïve chromatin without preexisting H3K9me3, are poorly understood. Here we show that Suv39h1’s CD (Suv39h1-CD) binds nucleic acids, and this binding is important for its function in heterochromatin assembly. Suv39h1-CD had higher binding affinity for RNA than DNA, and its ability to bind nucleic acids was independent of its H3K9me3 recognition. Suv39h1 bound major satellite RNAs in vivo, and knockdown of major satellite RNAs lowered Suv39h1 retention on pericentromere. Suv39h1 mutational studies indicated that both the nucleic acid–binding and H3K9me–binding activities of Suv39h1-CD were crucial for its pericentric heterochromatin assembly. These results suggest that chromatin-bound RNAs contribute to creating SUV39H’s target specificity. DOI: http://dx.doi.org/10.7554/eLife.25317.001
eLife digest Plants, animals and fungi store much of their DNA tightly packed with proteins in a form named heterochromatin. This arrangement helps to inactivate genes that are not needed in specific cells or at specific times, and provides a way to protect the genetic material from damage. Heterochromatin tends to form when an enzyme called a lysine methyltransferase chemically modifies some of the proteins associated with the DNA, which are known as histones. This enzyme modifies only some of the histones to get the process started, while a second protein then binds to the modified histones and causes more of the DNA to become packaged up as heterochromatin. In 2012, researchers reported that the version of the lysine methyltransferase enzyme from yeast binds to RNA molecules via a portion known as its chromodomain. Moreover, the enzyme needed to bind to RNA to help heterochromatin to form. A similar mechanism also occurs in fruit flies, another organism that is commonly studied in the laboratory. However, it was not clear if it happened in mammals like mice and humans. Now, Shirai, Kawaguchi et al. – who include many of the researchers involved in the 2012 study – report that the corresponding enzyme from mice can also bind to RNA molecules via its chromodomain. Further experiments showed that this activity was closely linked with the enzyme’s ability to target the correct histones and efficiently form heterochromatin. The first experiments were conducted using purified enzymes in the laboratory, while follow-up experiments looked at the enzyme’s activity within mouse cells. Other studies have previously reported that mutant mice lacking the lysine methyltransferase enzyme have defective heterochromatin, tend to die young and have genetic instabilities that are associated with an increased risk of tumors and male infertility. The new findings of Shirai, Kawaguchi et al. reveal that the mechanism behind the establishment of heterochromatin has mostly likely been conserved over a billion years of evolution, which is when yeast and mammals last shared a common ancestor. By revealing more about how mammalian cells can protect their DNA, these new findings could also mark an important step toward understanding and preventing birth defects that are caused when an embryo’s genetic material becomes damaged. DOI: http://dx.doi.org/10.7554/eLife.25317.002