The early 2000s witnessed a flourish in epigenetics research, driven by the discovery of numerous chromatin modifiers and readers and of the crucial role of RNA interference (RNAi) in establishing silent chromatin states. The fission yeast Schizosaccharomyces pombe, having a simple genome and many conserved heterochromatin factors, several of them encoded by single-copy genes, emerged as an ideal model organism for studying heterochromatin. This unique advantage attracted many researchers, including myself during my postdoctoral work.

The Moazed research group addressed this paradox in a landmark paper published in 2017. They focused on Clr4 (homolog of mammalian SUV39H), the sole H3K9 methyltransferase in S. pombe, which is responsible for catalysing all three methylation states (mono-, di- and trimethylation (H3K9me1–me3)). A crucial starting point was the known existence of a ‘switch position’ in H3K9 methyltransferases that dictates the degree of methylation. Mutation in the switch position of Clr4 resulted in a global loss of H3K9me3, whereas H3K9me2 was maintained. Notably, H3K9me2 was sufficient for recruiting the RNAi machinery, thereby enabling CTGS. However, heterochromatin in this mutant showed increased RNA polymerase II abundance and other histone modifications typically associated with active chromatin, accompanied by loss of transcriptional gene silencing (TGS).