Department of Biology, University of California, San Diego, La Jolla, CA, USA.
Nat Struct Mol Biol. 2011 Mar;18(3):302-8. doi: 10.1038/nsmb.1986. Epub 2011 Feb 6.
The highly conserved let-7 microRNA (miRNA) regulates developmental pathways across animal phyla. Mis-expression of let-7 causes lethality in C. elegans and has been associated with several human diseases. We show that timing of let-7 expression in developing worms is under complex transcriptional and post-transcriptional control. Expression of let-7 primary transcripts oscillates during each larval stage, but precursor and mature let-7 miRNAs do not accumulate until later in development after LIN-28 protein has diminished. We demonstrate that LIN-28 binds endogenous primary let-7 transcripts co-transcriptionally. We further show that LIN-28 binds endogenous primary let-7 transcripts in the nuclear compartment of human ES cells, suggesting that this LIN-28 activity is conserved across species. We conclude that co-transcriptional interaction of LIN-28 with let-7 primary transcripts blocks Drosha processing and, thus, precocious expression of mature let-7 during early development.
高度保守的 let-7 微 RNA（miRNA）调控着动物门的发育途径。let-7 的异常表达会导致秀丽隐杆线虫的致死，并与几种人类疾病有关。我们发现，发育中的线虫中 let-7 的表达时间受到复杂的转录和转录后调控。let-7 初级转录本在每个幼虫阶段都呈周期性表达，但前体和成熟的 let-7 miRNA 直到 LIN-28 蛋白减少后发育后期才积累。我们证明 LIN-28 与内源性初级 let-7 转录本共转录结合。我们进一步表明，LIN-28 在人胚胎干细胞的核区结合内源性初级 let-7 转录本，这表明这种 LIN-28 活性在物种间是保守的。我们的结论是，LIN-28 与 let-7 初级转录本的共转录相互作用阻止了 Drosha 的加工，从而导致早期发育中成熟 let-7 的过早表达。
