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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A network connecting Runx2, SATB2, and the miR-23a～27a～24-2 cluster regulates the osteoblast differentiation program
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A network connecting Runx2, SATB2, and the miR-23a～27a～24-2 cluster regulates the osteoblast differentiation program

机译：连接Runx2，SATB2和miR-23a〜27a〜24-2簇的网络调节成骨细胞的分化程序

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摘要

Induced osteogenesis includes a program of microRNAs (miRs) to repress the translation of genes that act as inhibitors of bone formation. How expression, of bone-related miRs is regulated remains a compelling question. Here we report that Runx2, a transcription factor essential for osteoblastogenesis, negatively regulates expression of the miR cluster 23a～27a～24-2. Overexpression, reporter, and chromatin immunoprecipitation assays established the presence of a functional Runx binding element that represses expression of these miRs. Consistent with this finding, exogenous expression of each of the miRs suppressed osteoblast differentiation, whereas antagomirs increased bone marker expression. The biological significance of Runx2 repression of this miR cluster is that each miR directly targets the 3' UTR of SATB2, which is known to synergize with Runx2 to facilitate bone formation. The findings suggest Runx2-negative regulation of multiple miRs by a feedforward mechanism to cause derepression of SATB2 to promote differentiation. We find also that miR-23a represses Runx2 in the terminally differentiated osteocyte, representing a feedback mechanism to attenuate osteoblast maturation. We provide direct evidence for an interdependent relationship among transcriptional inhibition of the miR cluster by Runx2, translational repression of Runx2 and of SATB2 by the cluster miRs during progression of osteoblast differentiation. Furthermore, miR cluster gain of function (i.e., inhibition of osteogenesis) is rescued by the exogenous expression of SATB2. Taken together, we have established a regulatory network with a central role for the miR cluster 23a～27a～24-2 in both progression and maintenance of the osteocyte phenotype.
机译：诱导成骨包括一个microRNA（miR）程序，以抑制充当骨形成抑制剂的基因的翻译。如何调节与骨相关的miR的表达仍然是一个令人信服的问题。在此我们报道Runx2是成骨细胞生成所必需的转录因子，它负调控miR簇23a〜27a〜24-2的表达。过表达，报道基因和染色质免疫沉淀测定法确定了可抑制这些miRs表达的功能性Runx结合元件的存在。与此发现一致，每个miR的外源表达抑制了成骨细胞的分化，而拟抑素增加了骨标志物的表达。该miR簇的Runx2抑制的生物学意义是每个miR直接靶向SATB2的3'UTR，已知它与Runx2协同作用以促进骨骼形成。这些发现提示通过前馈机制引起多个miR的Runx2负调控，从而引起SATB2抑制，从而促进分化。我们还发现，miR-23a在终末分化的骨细胞中抑制Runx2，代表减弱成骨细胞成熟的反馈机制。我们提供直接证据证明成骨细胞分化过程中Runx2对miR簇的转录抑制，Runx2和SATB2的翻译抑制受簇miRs相互依赖。此外，通过SATB2的外源表达挽救了miR簇的功能获得（即，抑制成骨作用）。综上所述，我们建立了一个miR簇23a〜27a〜24-2在骨细胞表型的发展和维持中起核心作用的调控网络。

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