TY - JOUR
T1 - Polycomb PRC2 complex mediates epigenetic silencing of a critical osteogenic master regulator in the hippocampus
AU - Aguilar, Rodrigo
AU - Bustos, Fernando J.
AU - Saez, Mauricio
AU - Rojas, Adriana
AU - Allende, Miguel L.
AU - van Wijnen, Andre J.
AU - van Zundert, Brigitte
AU - Montecino, Martin
N1 - Funding Information:
This work was supported by grants from FONDAP 15090007 (to M.M. and M.L.A.), FONDECYT 1130706 (to M.M.), FONDECYT 3150694 (to MS) and FONDECYT 1140301 (to B.vZ.). Additional funding was provided by NIH ( R01 AR049069 to A.J.vW.). R.A. and F.B. were supported by Doctoral Fellowships from CONICYT , Chile. A.R. was partially funded by Doctoral Fellowships from COLCIENCIAS and Pontificia Universidad Javeriana, Colombia .
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - Epigenetic regulation of gene expression
KW - Hippocampus
KW - Runx2
UR - http://www.scopus.com/inward/record.url?scp=84969983792&partnerID=8YFLogxK
U2 - 10.1016/j.bbagrm.2016.05.009
DO - 10.1016/j.bbagrm.2016.05.009
M3 - Article
AN - SCOPUS:84969983792
SN - 1874-9399
VL - 1859
SP - 1043
EP - 1055
JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
IS - 8
ER -