Bivalent chromatin modification

In recent years it has been suggested that the epigenetic program may play a key role in determining cell fate, including the decision to undergo self-renewal or commitment. Based on genome-wide chromatin immunoprecipitation (ChIP) studies combined with expression analysis, it has been suggested that the chromatin associated with many genes controlling lineage fate decisions is uniquely marked in stem cells. Their histone signature is referred to as bivalent as it includes modifications associated both with repression (H3K27me3) imposed by the polycomb group proteins (PcG), and activation (H3K4me3) encoded by the Set/MLL histone methyltransferase, the mammalian homologue of the trithorax group proteins (trxG) [1-6]. Despite having both “active” and ‘repressive’ chromatin marks, such genes were thought not to be expressed. Taken together, these observations led to an attractive model suggesting that a preimposed epigenetic signature suppresses expression of lineage control genes in stem cells (maintaining a pluripotent state) while at the same time ‘poising’ such genes for subsequent activation (reviewed in [7]). In favor of this, many lineage-control genes have a bivalent signature [1-5]. However, as the model has evolved, more recently it has been shown that RNA polymerase II (PolII) may be present but stalled at the promoters of bivalent genes [8, 9] and that short (abortive) transcripts may be detected at their promoters [10]. Furthermore, although embryonic stem cells (ES cells) lacking the PcG repressive complex 2 (PRC2) aberrantly express developmental regulators [11] they maintain pluripotency [12]. Similarly, two recent experiments in which components of the SET1/MLL core subunit (Dpy-30, RbBP5 and WDR5) were reduced to similar levels showed opposite phenotypes. In one chapter there was maintenance of self-renewal with a defect in differentiation [13], and in another there was a loss of selfrenewal [14]. Together these observations suggest that the current models explaining the significance bivalently marked chromatin may require revision.