Ezh2 is required for neural crest-derived cartilage and bone formation.
The emergence of craniofacial skeletal elements, and of the jaw in particular, was a crucial step in the evolution of higher vertebrates. Most facial bones and cartilage are generated during embryonic development by cranial neural crest cells, while an osteochondrogenic fate is suppressed in more posterior neural crest cells. Key players in this process are Hox genes, which suppress osteochondrogenesis in posterior neural crest derivatives. How this specific pattern of osteochondrogenic competence is achieved remains to be elucidated. Here we demonstrate that Hox gene expression and osteochondrogenesis are controlled by epigenetic mechanisms. Ezh2, which is a component of polycomb repressive complex 2 (PRC2), catalyzes trimethylation of lysine 27 in histone 3 (H3K27me3), thereby functioning as transcriptional repressor of target genes. Conditional inactivation of Ezh2 does not interfere with localization of neural crest cells to their target structures, neural development, cell cycle progression or cell survival. However, loss of Ezh2 results in massive derepression of Hox genes in neural crest cells that are usually devoid of Hox gene expression. Accordingly, craniofacial bone and cartilage formation is fully prevented in Ezh2 conditional knockout mice. Our data indicate that craniofacial skeleton formation in higher vertebrates is crucially dependent on epigenetic regulation that keeps in check inhibitors of an osteochondrogenic differentiation program.
Cell and Developmental Biology, Institute of Anatomy, University of Zurich, CH-8057 Zurich, Switzerland.
Daniel
D
Schwarz
Sandra
S
Varum
Martina
M
Zemke
Anne
A
Schöler
Arianna
A
Baggiolini
Kalina
K
Draganova
Haruhiko
H
Koseki
Dirk
D
Schübeler
Lukas
L
Sommer
D000423:Alcian Blue; D000818:Animals; D000880:Anthraquinones; D002356:Cartilage / Q000196:embryology*; D020219:Chondrogenesis / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000502:physiology*; D005147:Facial Bones / Q000196:embryology*; D005434:Flow Cytometry; D005697:Galactosides; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009432:Neural Crest / Q000378:metabolism / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
D000880:Anthraquinones; D005697:Galactosides; D006657:Histones; D007211:Indoles; C010078:alizarin; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D000423:Alcian Blue; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
Chondrogenesis; Epigenetic regulation; Ezh2; Mouse; Neural crest; Osteogenesis