Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA.
Mol Cell. 2013 Oct 10;52(1):101-12. doi: 10.1016/j.molcel.2013.08.027. Epub 2013 Sep 19.
Abundantly expressed in fetal tissues and adult muscle, the developmentally regulated H19 long noncoding RNA (lncRNA) has been implicated in human genetic disorders and cancer. However, how H19 acts to regulate gene function has remained enigmatic, despite the recent implication of its encoded miR-675 in limiting placental growth. We noted that vertebrate H19 harbors both canonical and noncanonical binding sites for the let-7 family of microRNAs, which plays important roles in development, cancer, and metabolism. Using H19 knockdown and overexpression, combined with in vivo crosslinking and genome-wide transcriptome analysis, we demonstrate that H19 modulates let-7 availability by acting as a molecular sponge. The physiological significance of this interaction is highlighted in cultures in which H19 depletion causes precocious muscle differentiation, a phenotype recapitulated by let-7 overexpression. Our results reveal an unexpected mode of action of H19 and identify this lncRNA as an important regulator of the major let-7 family of microRNAs.
在胎儿组织和成人肌肉中大量表达的发育调控长非编码 RNA（lncRNA）H19 已被牵连到人类遗传疾病和癌症中。然而，尽管其编码的 miR-675 最近被暗示限制胎盘生长，但 H19 如何作用来调节基因功能仍然是个谜。我们注意到，脊椎动物 H19 既具有经典的也具有非经典的 let-7 家族 microRNAs 的结合位点，let-7 在发育、癌症和代谢中发挥着重要作用。通过使用 H19 敲低和过表达，结合体内交联和全基因组转录组分析，我们证明 H19 通过充当分子海绵来调节 let-7 的可用性。在 H19 耗竭导致肌肉分化提前的培养物中，这种相互作用的生理意义得到了强调，而过表达 let-7 则再现了这一表型。我们的结果揭示了 H19 的一种意想不到的作用模式，并将这种 lncRNA 鉴定为主要的 let-7 家族 microRNAs 的重要调节剂。
