The bivalent hypothesis posits that genes encoding developmental regulators 
required for early lineage decisions are poised in stem/progenitor cells by the 
balance between a repressor histone modification (H3K27me3), mediated by the 
Polycomb Repressor Complex 2 (PRC2), and an activator modification (H3K4me3). In 
this study, we test whether this mechanism applies equally to genes that are not 
required until terminal differentiation. We focus on the RE1 Silencing 
Transcription Factor (REST) because it is expressed highly in stem cells and is 
an established global repressor of terminal neuronal genes. Elucidation of the 
REST complex, and comparison of chromatin marks and gene expression levels in 
control and REST-deficient stem cells, shows that REST target genes are poised 
by a mechanism independent of Polycomb, even at promoters which bear the 
H3K27me3 mark. Specifically, genes under REST control are actively repressed in 
stem cells by a balance of the H3K4me3 mark and a repressor complex that relies 
on histone deacetylase activity. Thus, chromatin distinctions between pro-neural 
and terminal neuronal genes are established at the embryonic stem cell stage by 
two parallel, but distinct, repressor pathways.