Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zürich, Zürich 8093, Switzerland.
Mol Cell. 2020 Dec 17;80(6):980-995.e13. doi: 10.1016/j.molcel.2020.10.023. Epub 2020 Nov 16.
Ribosomes have been suggested to directly control gene regulation, but regulatory roles for ribosomal RNA (rRNA) remain largely unexplored. Expansion segments (ESs) consist of multitudes of tentacle-like rRNA structures extending from the core ribosome in eukaryotes. ESs are remarkably variable in sequence and size across eukaryotic evolution with largely unknown functions. In characterizing ribosome binding to a regulatory element within a Homeobox (Hox) 5' UTR, we identify a modular stem-loop within this element that binds to a single ES, ES9S. Engineering chimeric, "humanized" yeast ribosomes for ES9S reveals that an evolutionary change in the sequence of ES9S endows species-specific binding of Hoxa9 mRNA to the ribosome. Genome editing to site-specifically disrupt the Hoxa9-ES9S interaction demonstrates the functional importance for such selective mRNA-rRNA binding in translation control. Together, these studies unravel unexpected gene regulation directly mediated by rRNA and how ribosome evolution drives translation of critical developmental regulators.
核糖体被认为可以直接控制基因调控，但核糖体 RNA（rRNA）的调节作用在很大程度上仍未得到探索。扩展片段（ES）由无数从真核生物核心核糖体伸出的触手状 rRNA 结构组成。ES 在真核生物进化过程中在序列和大小上具有显著的可变性，但其功能在很大程度上是未知的。在描述核糖体与 Homeobox（Hox）5'UTR 内的调节元件结合时，我们在该元件内鉴定出一个模块化的茎环结构，该结构与单个 ES，ES9S 结合。对 ES9S 进行嵌合“人源化”酵母核糖体的工程改造表明，ES9S 序列的进化赋予了 Hoxa9mRNA 与核糖体的种特异性结合。针对 Hoxa9-ES9S 相互作用的定点破坏的基因组编辑表明，这种选择性的 mRNA-rRNA 结合在翻译控制中具有重要功能。总之，这些研究揭示了 rRNA 直接介导的意想不到的基因调控，以及核糖体进化如何驱动关键发育调节剂的翻译。
