Unfortunately, the KISS principle (‘keep it simple, stupid’) doesn’t apply to chromatin. Although we’d like to think that certain histone modifications are always “good” for gene transcription and others are invariably “bad,” Barbara Panning and co-workers at the University of California San Francisco have found that in embryonic stem cells (ESCs), the transcriptional outcome of some genes depends on the finely tuned balance of activating and repressive histone modifications.
In a recent review in the journal Cell Cycle, the investigators describe how some genes, for example, developmental regulators, in many cell types are marked with both activating (H3 lysine 4 trimethylation; H3K4me3) and repressive (H3 lysine 27 trimethylation; H3K27me3) histone modifications. In ESCs, these ‘bivalent’ genes are transcribed at low levels but are primed for rapid activation upon receipt of the appropriate differentiation cues.
The histone acetyltransferase/histone exchange complex Tip60-p400 is required for normal self-renewal in mouse ESCs and localizes to sites marked by H3K4me3 (at both highly expressed genes and at bivalent genes expressed at low levels.) Surprisingly, Tip60-p400 represses differentiation-related genes in ESCs, despite its known function as a transcriptionally activating histone acetyltransferase.
Panning and colleagues hypothesize that Tip60-p400 might repress transcription by one of two mechanisms: Tip60-mediated acetylation and activation of an unknown transcriptional repressor, which overcomes the transcriptionally favorable acetylation of histone tails by Tip60; or Tip60-mediated acetylation of histone tails in combination with a second, unknown chromatin modification, both of which are required for the binding of an unknown transcriptional repressor to chromatin.
If your head is spinning from the complexity of it all, get the complete story at Cell Cycle, November 2008