Linking RNA structure and function

Published: Friday,9月9日,2016—05:17 in生物学与自然

Several years ago,biologists discovered a new type of genetic material known as long noncoding RNA.This RNA does not code for proteins and is copied from sections of the genome once believed to be "junk DNA." Since then,徳赢手机版scientists have found evidence that long noncoding RNA,or lncRNA,plays roles in many cellular processes,包括指导胚胎发育过程中的细胞命运。However,it has been unknown exactly how lncRNA exerts this influence.

Inspired by historical work showing that structure plays a role in the function of other classes of RNA such as transfer RNA,MIT biologists have now deciphered the structure of one type of lncRNA and used that information to figure out how it interacts with a cellular protein to control the development of heart muscle cells.This is one of first studies to link the structure of lncRNAs to their function.

"Emerging data points to fundamental roles for many of these molecules in development and disease,因此,我们认为,确定lncrnas的结构对于理解其功能是至关重要的,”Laurie Boyer说,the Irwin and Helen Sizer Career Development Associate Professor of Biology and Biological Engineering at MIT and the senior author of the study,which appears in the journalMolecular Cell9月9日8。

Learning more vwin徳赢app下载about how lncRNAs control cell differentiation could offer a new approach to developing drugs for patients whose hearts have been damaged by cardiovascular disease,aging,or cancer.

The paper's lead author is MIT postdoc Zhihong Xue.Other MIT authors are undergraduate Boryana Doyle and Sarnoff Fellow Arune Gulati.Scott HennellyIrina Novikovaand Karissa Sanbonmatsu of Los Alamos National Laboratory are also authors of the paper.

Probing the heart

Boyer's lab previously identified a mouse lncRNA known as Braveheart,与其他组织相比,在心脏中发现了更高的水平。In 2013,Boyer showed that this RNA molecule is necessary for normal development of heart muscle cells.

In the new study,the researchers decided to investigate which regions of the 600-nucleotide RNA molecule are crucial to its function.“我们知道勇敢的心对心肌细胞的发育至关重要,but we didn't know the detailed molecular mechanism of how this lncRNA functioned,so we hypothesized that determining its structure could reveal new clues," Xue says.

To determine Braveheart's structure,the researchers used a technique called chemical probing,in which they treated the RNA molecule with a chemical reagent that modifies exposed RNA nucleotides.通过分析哪些核苷酸与这种试剂结合,the researchers can identify single-stranded regions,双股螺旋,loops,and other structures.

This analysis revealed that Braveheart has several distinct structural regions,or motifs.研究人员随后测试了这些基序中哪一个对分子的功能最重要。令他们惊讶的是,他们发现去除11个核苷酸,composing a loop that represents just 2 percent of the entire molecule,halted normal heart cell development.

The researchers then searched for proteins that the Braveheart loop might interact with to control heart cell development.In a screen of vwin徳赢app下载about 10,000 proteins,他们发现一种被称为细胞核酸结合蛋白(CNBP)的转录因子蛋白与该区域紧密结合。以前的研究表明,CNBP的突变可导致小鼠和人类的心脏缺陷。

Further studies revealed that CNBP acts as a potential roadblock for cardiac development,勇敢的心释放了这个压抑者,allowing cells to become heart muscle.

Building a fingerprint

徳赢手机版科学家们还没有确定一种与老鼠勇敢心lncrna相对应的人类,部分原因是人类和老鼠的lncrna序列保存不良,even though protein-coding genes of the two species are usually very similar.However,now that the researchers know the structure of the mouse Braveheart lncRNA,他们计划分析人类的lncrna分子以识别相似的结构,which would suggest that they have similar functions.

"We're taking this motif and we're using it to build a fingerprint so we can potentially find motifs that resemble that lncRNA across species," Boyer says.“我们还希望扩展这项工作,以确定主题目录的作用模式,以便更好地预测具有重要功能的lncrna。”

The researchers also plan to apply what they have learned vwin徳赢app下载about lncRNA toward engineering new therapeutics."We fully expect that unraveling lncRNA structure-to-function relationships will open up exciting new therapeutic modalities in the near future," Boyer says.

Source:Massachusetts Institute of Technology



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