Polycomb PRC2 complex mediates epigenetic silencing of a critical osteogenic master regulator in the hippocampus

• Published in: Biochimica et biophysica acta Vol. 1859; no. 8; pp. 1043 - 1055
• Main Authors: Aguilar, Rodrigo, Bustos, Fernando J., Saez, Mauricio, Rojas, Adriana, Allende, Miguel L., van Wijnen, Andre J., van Zundert, Brigitte, Montecino, Martin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2016
• Subjects: Aging - genetics; Aging - metabolism; Animals; Animals, Newborn; Cell Differentiation; Chromatin - chemistry; Chromatin - metabolism; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Cyclin-Dependent Kinase Inhibitor p57 - genetics; Cyclin-Dependent Kinase Inhibitor p57 - metabolism; Embryo, Mammalian; Epigenetic regulation of gene expression; Gene Expression Regulation, Developmental; Gene Silencing; Hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Histones - genetics; Histones - metabolism; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Neurons - cytology; Neurons - metabolism; Osteoblasts - cytology; Osteoblasts - metabolism; Osteogenesis - genetics; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Runx2; Hippocampus; Epigenetic regulation of gene expression; Runx2
• ISSN: 1874-9399; 0006-3002; 1876-4320
• DOI: 10.1016/j.bbagrm.2016.05.009

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. •The osteogenic master gene Runx2 is epigenetically repressed in hippocampus.•Complementary epigenetic mechanisms progressively silence Runx2.•Knockdown of PRC2 activates Runx2 expression in hippocampal cells.•Overexpression of Wdr5-containing Trithorax complexes overrules Runx2 silencing.