Systematic Discovery of Structural Elements Governing Mammalian mRNA Stability

Decoding post-transcriptional regulatory programs in RNA is a critical step in the larger goal to develop predictive dynamical models of cellular behavior. Despite recent efforts(1–3), the vast landscape of RNA regulatory elements remain largely uncharacterized. A longstanding obstacle is the contribution of local RNA secondary structure in defining interaction partners in a variety of regulatory contexts, including but not limited to transcript stability(3), alternative splicing(4) and localization(3). There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (e.g. human cardiac troponin T) or affects other aspects of RNA biology(5). Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence(3,6). We have developed a computational framework based on context-free grammars(3,7) and mutual information(2) that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behavior. The application of this framework to genome-wide mammalian mRNA stability data revealed eight highly significant elements with substantial structural information, for the strongest of which we showed a major role in global mRNA regulation. Through biochemistry, mass-spectrometry, and in vivo binding studies, we identified HNRPA2B1 as the key regulator that binds this element and stabilizes a large number of its target genes. Ultimately, 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 can also be employed to reveal the structural elements that modulate other aspects of RNA behavior.