Zhao Wenxue, Pollack Joshua L, Blagev Denitza P, Zaitlen Noah, McManus Michael T, Erle David J
Lung Biology Center, University of California San Francisco, San Francisco, California, USA.
1] Diabetes Center, University of California San Francisco, San Francisco, California, USA. [2] Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA.
Nat Biotechnol. 2014 Apr;32(4):387-91. doi: 10.1038/nbt.2851. Epub 2014 Mar 16.
Functional characterization of noncoding sequences is crucial for understanding the human genome and learning how genetic variation contributes to disease. 3' untranslated regions (UTRs) are an important class of noncoding sequences, but their functions remain largely uncharacterized. We developed a method for massively parallel functional annotation of sequences from 3' UTRs (fast-UTR) and used this approach to measure the effects of a total of >450 kilobases of 3' UTR sequences from >2,000 human genes on steady-state mRNA abundance, mRNA stability and protein production. We found widespread regulatory effects on mRNA that were coupled to effects on mRNA stability and protein production. Furthermore, we discovered 87 novel cis-regulatory elements and measured the effects of genetic variation within known and novel 3' UTR motifs. This work shows how massively parallel approaches can improve the functional annotation of noncoding sequences, advance our understanding of cis-regulatory mechanisms and quantify the effects of human genetic variation.
非编码序列的功能表征对于理解人类基因组以及了解遗传变异如何导致疾病至关重要。3'非翻译区（UTR）是一类重要的非编码序列，但其功能在很大程度上仍未得到充分表征。我们开发了一种对3'UTR序列进行大规模平行功能注释的方法（fast-UTR），并使用该方法来测量来自2000多个人类基因的总计超过450千碱基的3'UTR序列对稳态mRNA丰度、mRNA稳定性和蛋白质产生的影响。我们发现对mRNA存在广泛的调控作用，这些作用与对mRNA稳定性和蛋白质产生的影响相关联。此外，我们发现了87个新的顺式调控元件，并测量了已知和新的3'UTR基序内遗传变异的影响。这项工作展示了大规模平行方法如何能够改善非编码序列的功能注释，推进我们对顺式调控机制的理解，并量化人类遗传变异的影响。
