Publication Date:
2012-04-13
Description:
Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including--but not limited to--transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350620/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350620/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goodarzi, Hani -- Najafabadi, Hamed S -- Oikonomou, Panos -- Greco, Todd M -- Fish, Lisa -- Salavati, Reza -- Cristea, Ileana M -- Tavazoie, Saeed -- 2R01HG003219/HG/NHGRI NIH HHS/ -- DP1 DA026192/DA/NIDA NIH HHS/ -- DP1 OD003787/OD/NIH HHS/ -- DP1 OD003787-05/OD/NIH HHS/ -- R01 HG003219/HG/NHGRI NIH HHS/ -- R01 HG003219-08/HG/NHGRI NIH HHS/ -- T32-GM066699/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Apr 8;485(7397):264-8. doi: 10.1038/nature11013.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22495308" target="_blank"〉PubMed〈/a〉
Keywords:
3' Untranslated Regions/genetics/physiology
;
Algorithms
;
Animals
;
Breast Neoplasms/genetics
;
Cell Line, Tumor
;
Gene Expression Profiling
;
Gene Expression Regulation, Neoplastic
;
Gene Knockdown Techniques
;
Genome, Human/genetics
;
Genomics
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Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics/metabolism
;
Humans
;
Mice
;
*Nucleic Acid Conformation
;
Nucleotide Motifs
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*RNA Stability/genetics
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RNA, Messenger/chemistry/*genetics/*metabolism
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RNA, Small Interfering
;
Time Factors
;
Transcription, Genetic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
