Histone methylation keeps heterochromatin condensed and the genes within silent. Yet the same methylation patterns are passed on to daughter cells. This inheritence requires RNA interference—and thus transcription. “That's a paradox we've been looking at for several years,” says Martienssen. To resolve the paradox, the authors examined yeast centromeres for changes in RNA transcripts, histone modifications, and RNAi activity throughout the cell cycle.
As they enter G2, methylated histones at the centromere link to a major heterchromatin structural protein called Swi6, which in turn binds to cohesin, thereby tying the replicated chromosomes together. But during mitosis, histone phosphorylation knocks off Swi6; its removal is a prerequisite for transcription. The authors showed that this loss of Swi6 was accompanied by histone demethylation, which is also required for transcription. After passing through G1, the exposed centromeric sequences were transcribed during very early S phase. The transcripts were quickly processed by the RNAi machinery into siRNAs, which the authors had previously shown directs the methylation machinery back to the same demethylated histones at the transcribed centromeric sequences. So by the end of S phase, those sequences were remethylated and beginning to rebind Swi6 and cohesin, forming true heterochromatin again.
The timing makes sense. “S phase is exactly when you would need to modify histones to inherit epigenetic modifications,” says Martienssen, since that is when both copies can be targeted at once.
The authors also showed that temperature elevation inhibited the whole process. If the same is true in other systems, it might explain why some plants require a cold period before they can flower. This necessity depends on RNAi silencing and heterochromatin and requires cell division, suggesting that cold-driven gene modifications inherited during the winter trigger flowering in the spring.