During hippocampal neuron differentiation, the expression of critical inducers 
of non-neuronal cell lineages must be efficiently silenced. Runx2 transcription 
factor is the master regulator of mesenchymal cells responsible for 
intramembranous osteoblast differentiation and formation of the craniofacial 
bone tissue that surrounds and protects the central nervous system (CNS) in 
mammalian embryos. The molecular mechanisms that mediate silencing of the Runx2 
gene and its downstream target osteogenic-related genes in neuronal cells have 
not been explored. Here, we assess the epigenetic mechanisms that mediate 
silencing of osteoblast-specific genes in CNS neurons. In particular, we address 
the contribution of histone epigenetic marks and histone modifiers on the 
silencing of the Runx2/p57 bone-related isoform in rat hippocampal tissues at 
embryonic to adult stages. Our results indicate enrichment of repressive 
chromatin histone marks and of the Polycomb PRC2 complex at the Runx2/p57 
promoter region. Knockdown of PRC2 H3K27-methyltransferases Ezh2 and Ezh1, or 
forced expression of the Trithorax/COMPASS subunit Wdr5 activates Runx2/p57 mRNA 
expression in both immature and mature hippocampal cells. Together these results 
indicate that complementary epigenetic mechanisms progressively and efficiently 
silence critical osteoblastic genes during hippocampal neuron differentiation.