Evidence That Up-Regulation of MicroRNA-29 Contributes to Postnatal Body Growth Deceleration
Evidence That Up-Regulation of MicroRNA-29 Contributes to Postnatal Body Growth Deceleration
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DOI：
10.1210/me.2015-1047
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发表时间：
2015-06-01
影响因子：
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通讯作者：
Lui, Julian C.
中科院分区：
文献类型：
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作者：
Kamran, Fariha;Andrade, Anenisia C.;Lui, Julian C.
婴儿期身体生长迅速，但随后由于多个器官中同时发生的细胞增殖的进行性下降而减慢并最终停止。我们先前表明，这种增殖的下降部分是由出生后多个器官中大量生长促进基因的下调驱动的。我们假设这种限制生长的遗传程序是由microRNAs（miRNAs）协调的。生物信息学分析确定了miR-29家族的miRNA的靶序列在年龄下调基因中过度表达。同时，小鼠肾脏和肺中的表达微阵列分析显示，miR-29家族的所有成员，miR-29 a、-B和-c，在1至6周龄时均强烈上调。Real-time PCR证实，miR-29 a、-B和-c在肝、肾、肺和心脏中随着年龄的增长而上调，并且它们在从5周龄小鼠分离的肝细胞中的表达水平高于从胚胎16.5天的胚胎小鼠肝分离的肝细胞。接下来，我们关注了3个预测的miR-29靶基因（Igf 1，Imp 1和Mest），所有这些都是促进生长的。将含有来自每个基因的预测靶序列的3 '-非翻译区单独置于荧光素酶报告基因构建体中。miR-29模拟物的转染抑制了所有3种基因的荧光素酶基因活性，并且这种抑制通过突变靶序列而减弱，表明这些基因确实受miR-29调节。总之，研究结果表明，在青少年生活中miR-29的上调驱动了多种生长促进基因的下调，从而导致生理减缓和最终停止身体生长。
Body growth is rapid in infancy but subsequently slows and eventually ceases due to a progressive decline in cell proliferation that occurs simultaneously in multiple organs. We previously showed that this decline in proliferation is driven in part by postnatal down-regulation of a large set of growth-promoting genes in multiple organs. We hypothesized that this growth-limiting genetic program is orchestrated by microRNAs (miRNAs). Bioinformatic analysis identified target sequences of the miR-29 family of miRNAs to be overrepresented in age-down-regulated genes. Concomitantly, expression microarray analysis in mouse kidney and lung showed that all members of the miR-29 family, miR-29a, -b, and -c, were strongly up-regulated from 1 to 6 weeks of age. Real-time PCR confirmed that miR-29a, -b, and -c were up-regulated with age in liver, kidney, lung, and heart, and their expression levels were higher in hepatocytes isolated from 5-week-old mice than in hepatocytes from embryonic mouse liver at embryonic day 16.5. We next focused on 3 predicted miR-29 target genes (Igf1, Imp1, and Mest), all of which are growth-promoting. A 3'-untranslated region containing the predicted target sequences from each gene was placed individually in a luciferase reporter construct. Transfection of miR-29 mimics suppressed luciferase gene activity for all 3 genes, and this suppression was diminished by mutating the target sequences, suggesting that these genes are indeed regulated by miR-29. Taken together, the findings suggest that up-regulation of miR-29 during juvenile life drives the down-regulation of multiple growth-promoting genes, thus contributing to physiological slowing and eventual cessation of body growth.