TY - JOUR
T1 - Genome-wide screening in human growth plates during puberty in one patient suggests a role for RUNX2 in epiphyseal maturation
AU - Emons, Joyce
AU - Dutilh, Bas E.
AU - Decker, Eva
AU - Pirzer, Heide
AU - Sticht, Carsten
AU - Gretz, Norbert
AU - Rappold, Gudrun
AU - Cameron, Ewan R.
AU - Neil, James C.
AU - Stein, Gary S.
AU - van Wijnen, Andre J.
AU - Wit, Jan Maarten
AU - Post, Janine N.
AU - Karperien, Marcel
N1 - Funding Information:
Paula Yoon, Ronald Rosenberg, William Mac Kenzie, Data, Analytics, and Modeling Task Force; Rebecca Leeb, Community Intervention and Critical Populations Task Force.
PY - 2011/5
Y1 - 2011/5
N2 - 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.
AB - 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.
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U2 - 10.1530/JOE-10-0219
DO - 10.1530/JOE-10-0219
M3 - Article
C2 - 21307122
AN - SCOPUS:79955526975
SN - 0022-0795
VL - 209
SP - 245
EP - 254
JO - Journal of Endocrinology
JF - Journal of Endocrinology
IS - 2
ER -