Roush Sarah F, Slack Frank J
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
Dev Biol. 2009 Oct 15;334(2):523-34. doi: 10.1016/j.ydbio.2009.07.012. Epub 2009 Jul 21.
The let-7 family of microRNAs (miRNAs) are important regulators of developmental timing and cell differentiation and are often misexpressed in human cancer. In C. elegans, let-7 controls cell fate transitions from larval stage 4 (L4) to adulthood by post-transcriptionally down-regulating lineage-abnormal 41 (lin-41) and hunchback-like 1 (hbl-1). Primary let-7 (pri-let-7) transcripts are up-regulated in the L3, yet little is known about what controls this transcriptional up-regulation. We sought factors that either turn on let-7 transcription or keep it repressed until the correct time. Here we report that one of let-7's targets, the transcription factor Hunchback-like 1 (HBL-1), is responsible for inhibiting the transcription of let-7 in specific tissues until the L3. hbl-1 is a known developmental timing regulator and inhibits adult development in larval stages. Therefore, one important function of HBL-1 in maintaining larval stage fates is inhibition of let-7. Indeed, our results reveal let-7 as the first known target of the HBL-1 transcription factor in C. elegans and suggest a negative feedback loop mechanism for let-7 and HBL-1 regulation.
微小RNA（miRNA）的let-7家族是发育时间和细胞分化的重要调节因子，在人类癌症中常常表达异常。在秀丽隐杆线虫中，let-7通过转录后下调谱系异常41（lin-41）和驼背样1（hbl-1）来控制细胞命运从幼虫4期（L4）向成虫期的转变。初级let-7（pri-let-7）转录本在L3期上调，但对于控制这种转录上调的因素知之甚少。我们寻找能够开启let-7转录或在正确时间之前使其保持抑制状态的因子。在此我们报告，let-7的一个靶标，转录因子驼背样1（HBL-1），负责在特定组织中抑制let-7的转录直至L3期。hbl-1是一种已知的发育时间调节因子，在幼虫阶段抑制成虫发育。因此，HBL-1在维持幼虫阶段命运中的一个重要功能是抑制let-7。事实上，我们的结果揭示let-7是秀丽隐杆线虫中HBL-1转录因子的首个已知靶标，并提示了let-7和HBL-1调节的负反馈环机制。
