Unknown,Transcriptomics,Genomics,Proteomics

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Genome wide screening of human growth plates during early and progressed stage puberty in one patient

ABSTRACT: In progressed puberty, estrogen is responsible for the deceleration of growth by stimulating growth plate maturation. The mechanism of action is largely unknown. We obtained pubertal growth plate specimens of the same girl at Tanner stage B2 and Tanner stage B3, which allowed us to address this issue in more detail. Histological analysis showed that progression of puberty coincided with characteristic morphological changes associated with growth plate maturation, such as decreases in total growth plate height (p=0.002), height of the individual zones (p<0.001) and a increase in intercolumnar space (p<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated, 28% downregulated) changing with progression of puberty. Overall changes in gene expression were small (average 1.1 fold change). The 394 genes mapped to 13 significantly changing pathways (p<0.05) in majority belonging to extracellular matrix, cell cycle and cell death, which are all related to growth plate maturation. We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionary conserved binding sites for transcription factors implemented in growth plate maturation such as Estrogen Receptor, Androgen Receptor, Elk1, Stat5b, CREBP and Runx2. Runx2 and Elk1, but not estrogen receptor binding sites were enriched and were present in 87 and 43 out of the 394 genes, respectively.In conclusion, our data suggest a role for Runx2 and Elk1 in growth plate maturation and provides suggestive evidence that the effect of estrogen on growth plate maturation is not mediated by activating genomic estrogen signalling in growth plate chondrocytes. 2 replicate samples for each developmental stage for a total of 6 samples

ORGANISM(S): Homo sapiens

SUBMITTER: joyce emons

PROVIDER: E-GEOD-18338 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Human adult height reflects the outcome of childhood skeletal growth. Growth plate (epiphyseal) chondrocytes are key determinants of height. As epiphyseal chondrocytes mature and proliferate, they pass through three developmental stages, which are organized into three distinct layers in the growth plate: (i) resting (round), (ii) proliferative (flat), and (iii) hypertrophic. Recent genomewide association studies (GWASs) of human height identified numerous associated loci, which are enriched for genes expressed in growth plate chondrocytes. However, it remains unclear which specific genes expressed in which layers of the growth plate regulate skeletal growth and human height. To connect the genetics of height and growth plate biology, we analyzed GWAS data through the lens of gene expression in the three dissected layers of murine newborn tibial growth plate. For each gene, we derived a specificity score for each growth plate layer and regressed these scores against gene-level p values from recent height GWAS data. We found that specificity for expression in the round cell layer, which contains chondrocytes early in maturation, is significantly associated with height GWAS p values (p = 8.5 × 10−9); this association remains after conditioning on specificity for the other cell layers. The association also remains after conditioning on membership in an “Online Mendelian Inheritance in Man (OMIM) gene set” (genes known to cause monogenic skeletal growth disorders, p < 9.7 × 10−6). We replicated the association in RNA-sequencing (RNA-seq) data from maturing chondrocytes sampled at early and late time points during differentiation in vitro: we found that expression early in differentiation is significantly associated with p values from height GWASs (p = 6.1 × 10−10) and that this association remains after conditioning on expression at 10 days in culture and on the OMIM gene set (p < 0.006). These findings newly implicate genes highlighted by GWASs of height and specifically expressed in the round cell layer as being potentially important regulators of skeletal biology. © 2021 American Society for Bone and Mineral Research (ASBMR).

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Genome wide screening of human growth plates during early and progressed stage puberty in one patient

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