title: Genome-wide screening in human growth plates during puberty in one patient suggests a role for RUNX2 in epiphyseal maturation.
abstract: In late puberty, estrogen decelerates bone growth by stimulating growth plate maturation. In this study, we analyzed the mechanism of estrogen action using two pubertal growth plate specimens of one girl at Tanner stage B2 and Tanner stage B3. Histological analysis showed that progression of puberty coincided with characteristic morphological changes: a decrease in total growth plate height (P=0.002), height of the individual zones (P<0.001), and an increase in intercolumnar space (P<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated and 28% downregulated) that changed with the progression of puberty. Overall changes in gene expression were small (average 1.38-fold upregulated and 1.36-fold downregulated genes). The 394 genes mapped to 13 significantly changing pathways (P<0.05) associated with growth plate maturation (e.g. extracellular matrix, cell cycle, and cell death). We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionarily conserved binding sites for transcription factors implicated in growth plate maturation such as estrogen receptor (ER), androgen receptor, ELK1, STAT5B, cyclic AMP response element (CREB), and RUNX2. High-quality motif sites for RUNX2 (87 genes), ELK1 (43 genes), and STAT5B (31 genes), but not ER, were evolutionarily conserved, indicating their functional relevance across primates. Moreover, we show that some of these sites are direct target genes of these transcription factors as shown by ChIP assays.
authors.affiliation: Department of Paediatrics, Leiden University Medical Center, 2300 ZA Leiden, The Netherlands. j.emons@lumc.nl
authors.forename: Joyce
authors.initials: J
authors.lastname: Emons
authors.forename: Bas E
authors.initials: BE
authors.lastname: Dutilh
authors.forename: Eva
authors.initials: E
authors.lastname: Decker
authors.forename: Heide
authors.initials: H
authors.lastname: Pirzer
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Gudrun
authors.initials: G
authors.lastname: Rappold
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Cameron
authors.forename: James C
authors.initials: JC
authors.lastname: Neil
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Jan Maarten
authors.initials: JM
authors.lastname: Wit
authors.forename: Janine N
authors.initials: JN
authors.lastname: Post
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
mesh_terms: D000293:Adolescent; D041923:Adolescent Development; D002648:Child; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015894:Genome, Human; D006132:Growth Plate / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism*; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D006728:Hormones; C493709:RUNX2 protein, human; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I