title: Systematic discovery of structural elements governing stability of mammalian messenger RNAs.
abstract: 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.
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA.
authors.forename: Hani
authors.initials: H
authors.lastname: Goodarzi
authors.forename: Hamed S
authors.initials: HS
authors.lastname: Najafabadi
authors.forename: Panos
authors.initials: P
authors.lastname: Oikonomou
authors.forename: Todd M
authors.initials: TM
authors.lastname: Greco
authors.forename: Lisa
authors.initials: L
authors.lastname: Fish
authors.forename: Reza
authors.initials: R
authors.lastname: Salavati
authors.forename: Ileana M
authors.initials: IM
authors.lastname: Cristea
authors.forename: Saeed
authors.initials: S
authors.lastname: Tavazoie
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000502:physiology; D000465:Algorithms; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D015894:Genome, Human / Q000235:genetics; D023281:Genomics; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009690:Nucleic Acid Conformation; D059372:Nucleotide Motifs; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C439768:hnRNP A2