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H Goodarzi, HS Najafabadi, P Oikonomou, TM Greco, L Fish, R Salavati, IM Cristea and S Tavazoie
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.
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RNA splicing, Intron, Secondary structure, Cis-regulatory element, Gene expression, DNA, Messenger RNA, RNA
MeSH headings
3' Untranslated Regions, Algorithms, Animals, Breast Neoplasms, Cell Line, Tumor, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Genome, Human, Genomics, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Humans, Mice, Nucleic Acid Conformation, Nucleotide Motifs, RNA Stability, RNA, Messenger, RNA, Small Interfering, Time Factors, Transcription, Genetic
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