Children grow taller because their bones get longer. This bone elongation occurs at the growth plate, a thin layer of cartilage within juvenile bones. We previously reported evidence that the growth plate contains progenitor cells located within the resting zone. Children stop growing taller because the growth plate cartilage undergoes programmed senescence which involves extensive changes in gene expression, declining chonodrocyte proliferation, altered chonodrocyte differentiation, and involution of the growth plate. Eventually growth plate senescence leads to cessation of bone elongation and epiphyseal fusion. Estrogen accelerates this developmental process, causing growth to stop earlier. We found evidence that senescence occurs because progenitor cells in the resting zone of the growth plate are depleted in number and that estrogen acts by accelerating this depletion. These findings provide insight into the fundamental mechanisms that cause childhood linear growth to stop and into the endocine regulation of this process. Body size varies enormously among mammalian species. In small mammals, body growth is typically suppressed rapidly, within weeks, whereas in large mammals, growth is suppressed slowly, over years, allowing for a greater adult size. We previously reported evidence that body growth suppression in rodents is caused in part by a juvenile genetic program that occurs in multiple tissues simultaneously and involves the downregulation of a large set of growth-promoting genes. Recently, we found evidence that this genetic program is conserved among mammalian species but that its time course is evolutionarily modulated such that, in large mammals, it plays out more slowly, allowing for more prolonged growth and therefore greater body size. We have also explored epigenetic mechanisms that may orchestrate this juvenile growth-regulating genetic program. Using chromatin immunoprecipitation-promoter tiling array, we found extensive genome-wide shifts in H3K4 and H3K27 histone methylation occurring with age. Temporal changes in H3K4 trimethylation showed a strong, positive association with changes in gene expression, assessed by microarray, whereas changes in H3K27 trimethylation showed a negative association. Genes with decreases in H3K4 trimethylation with age were strongly implicated in cell cycle and cell proliferation functions. Taken together, the findings suggest that the common core developmental program of gene expression which occurs in multiple organs during juvenile life is associated with a common core developmental program of histone methylation. In particular, declining H3K4 trimethylation is strongly associated with gene downregulation and occurs in the promoter regions of many growth-regulating genes, suggesting that this change in histone methylation may contribute to the component of the genetic program that drives juvenile body growth deceleration. In some children with subnormal linear growth, a cause can be identified, but in many the etiology remains unknown. This condition, idiopathic short stature (ISS), can sometimes be severe. One goal of our group is to uncover the causes of this growth failure. Recently, we used whole-exome sequencing to study three families with autosomal dominant short stature, advanced bone age, and premature growth cessation. In these families, we identified novel heterozygous mutations in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. Our study demonstrated that heterozygous mutations in ACAN can cause a skeletal dysplasia which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the child who presents with short stature and accelerated skeletal maturation.
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