Regulation Of Childhood Growth

孩子们长得高是因为他们的骨头变长了。这种骨骼的延长发生在生长板，即幼年骨骼中的一层薄薄的软骨。我们以前报道的证据表明，生长板含有祖细胞位于休息区。儿童停止长高是因为生长板软骨经历程序性衰老，这涉及基因表达的广泛变化、软骨细胞增殖下降、软骨细胞分化改变和生长板退化。最终生长板衰老导致骨伸长和骨骺融合的停止。雌激素加速了这一发育过程，导致生长提前停止。我们发现衰老的发生是因为生长板静止区的祖细胞数量减少，而雌激素通过加速这种减少而起作用。这些发现提供了对导致儿童线性生长停止的基本机制的深入了解，以及对这一过程的内分泌调节。 不同哺乳动物的体型差异很大。在小型哺乳动物中，身体生长通常在数周内被迅速抑制，而在大型哺乳动物中，生长被缓慢抑制，多年来，允许更大的成年体型。我们以前报告的证据表明，啮齿动物的身体生长抑制部分是由一个少年的遗传程序，同时发生在多个组织，涉及一个大的生长促进基因的下调。最近，我们发现证据表明，这种遗传程序在哺乳动物物种中是保守的，但它的时间进程是进化调制的，在大型哺乳动物中，它发挥得更慢，允许更长的增长，因此更大的体型。 我们还探索了可能协调这种青少年生长调节遗传程序的表观遗传机制。使用染色质免疫沉淀-启动子平铺阵列，我们发现随着年龄的增长，H3 K4和H3 K27组蛋白甲基化发生了广泛的全基因组变化。通过微阵列评估，H3 K4三甲基化的时间变化与基因表达的变化表现出强烈的正相关，而H3 K27三甲基化的变化表现出负相关。随着年龄的增长，H3 K4三甲基化降低的基因与细胞周期和细胞增殖功能密切相关。总之，研究结果表明，在青少年生活中发生在多个器官中的基因表达的共同核心发育程序与组蛋白甲基化的共同核心发育程序相关。特别是，下降的H3 K4三甲基化与基因下调密切相关，并发生在许多生长调节基因的启动子区域，这表明组蛋白甲基化的这种变化可能有助于驱动青少年身体生长减速的遗传程序的组成部分。 在一些儿童低于正常的线性增长，可以确定的原因，但在许多病因仍然不明。这种情况，特发性身材矮小（ISS），有时可能是严重的。我们小组的一个目标是揭示这种增长失败的原因。最近，我们使用全外显子组测序来研究三个常染色体显性遗传性身材矮小、骨龄提前和过早生长停止的家族。在这些家族中，我们发现了ACAN的新杂合突变，ACAN编码聚集蛋白聚糖，生长板和其他软骨组织细胞外基质中的蛋白聚糖。我们的研究表明，ACAN杂合子突变可导致骨骼发育不良，临床表现为身材矮小伴骨龄提前。骨骼成熟的加速效应以前没有注意到在人类ACAN突变的少数报告。因此，我们的研究结果扩大了ACAN缺陷的范围，并为出现身材矮小和骨骼加速成熟的儿童提供了新的分子遗传病因学。

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.