title: Polycomb PRC2 complex mediates epigenetic silencing of a critical osteogenic master regulator in the hippocampus.
abstract: 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.
authors.affiliation: Center for Biomedical Research, Universidad Andres Bello, Santiago 8370146, Chile; FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago 8370146, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Aguilar
authors.affiliation: Center for Biomedical Research, Universidad Andres Bello, Santiago 8370146, Chile; FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago 8370146, Chile.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Bustos
authors.affiliation: Center for Biomedical Research, Universidad Andres Bello, Santiago 8370146, Chile; FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago 8370146, Chile.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Saez
authors.affiliation: Center for Biomedical Research, Universidad Andres Bello, Santiago 8370146, Chile; FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago 8370146, Chile.
authors.forename: Adriana
authors.initials: A
authors.lastname: Rojas
authors.affiliation: FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago 8370146, Chile; Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago 7800003, Chile.
authors.forename: Miguel L
authors.initials: ML
authors.lastname: Allende
authors.affiliation: Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Center for Biomedical Research, Universidad Andres Bello, Santiago 8370146, Chile.
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Zundert
authors.affiliation: Center for Biomedical Research, Universidad Andres Bello, Santiago 8370146, Chile; FONDAP Center for Genome Regulation, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago 8370146, Chile. Electronic address: mmontecino@unab.cl.
authors.forename: Martin
authors.initials: M
authors.lastname: Montecino
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002843:Chromatin; D050659:Core Binding Factor Alpha 1 Subunit; D050761:Cyclin-Dependent Kinase Inhibitor p57; D006657:Histones; C493717:Runx2 protein, rat; D063151:Polycomb Repressive Complex 2
keywords: Epigenetic regulation of gene expression; Hippocampus; Runx2