Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality in the developed world. Smoking is an important risk factor for the disease, but genetics determine outcome and disease severity. A significant and broad challenge in establishing the causal molecular mechanism from genetic association data is the fact that a majority of COPD-associated variants map to non-coding regions of the human genome. One of the genes strongly associated with COPD is SERPINA1, which encodes the a-1 antitrypsin protein. The SERPINA1 gene is remarkably complex: It has eleven splice variants, all of which change the 5'-untranslated region (5'-UTR) without altering the sequence of the encoded protein. We found that translation efficiencies of the mRNAs varied by orders of magnitude due to the strengths of upstream RNA structure and of open reading frames (uORFs). uORFs are found in roughly 50% of human genes and tend to function to reduce translation of the downstream gene but, other than this observation, are poorly understood mechanistically. We have developed and parameterized a structure-based leaky scanning model of translation that considers alternative splicing, uORF Kozak sequence strength, the RNA structure at the initiation site of uORFs, and the efficiency of translation of the primary open reading frame. We propose in our first aim to define how RNA structure and alternative splicing control expression of a-1 antitrypsin and extend this approach to two other COPD-associated genes. In our second aim we will comprehensively characterize the RNA structural elements in the SERPINA1 mRNA 5'-UTRs and in two other COPD-related mRNAs that control translation efficiency, without and with uORFs. These experiments will establish accurate and broadly impactful frameworks to define the RNA structural features that modulate translation efficiency in 5'-UTRs and will refine ribosomal leaky scanning models to better predict tissue-specific expression of COPD-associated proteins.
In many cases, protein synthesis efficiency is governed by the amount and location of structure in the untranslated regions (UTRs) of an mRNA. In this project, we will generate functional and structural models for mRNAs related to chronic obstructive pulmonary disease (COPD). These models will establish accurate and broadly impactful computational frameworks to define the RNA structural features that modulate translation efficiency in 5'-UTRs and will create a resource for identifying causative variants in precision medicine.
|Lackey, Lela; Coria, Aaztli; Woods, Chanin et al. (2018) Allele-specific SHAPE-MaP assessment of the effects of somatic variation and protein binding on mRNA structure. RNA 24:513-528|
|Gamache, Eric R; Doh, Jung H; Ritz, Justin et al. (2017) Structure-Function Model for Kissing Loop Interactions That Initiate Dimerization of Ty1 RNA. Viruses 9:|
|Woods, Chanin T; Lackey, Lela; Williams, Benfeard et al. (2017) Comparative Visualization of the RNA Suboptimal Conformational Ensemble In Vivo. Biophys J 113:290-301|
|Woods, Chanin Tolson; Laederach, Alain (2017) Classification of RNA structure change by 'gazing' at experimental data. Bioinformatics 33:1647-1655|
|Ball, Christopher B; Solem, Amanda C; Meganck, Rita M et al. (2017) Impact of RNA structure on ZFP36L2 interaction with luteinizing hormone receptor mRNA. RNA 23:1209-1223|
|Kutchko, Katrina M; Laederach, Alain (2017) Transcending the prediction paradigm: novel applications of SHAPE to RNA function and evolution. Wiley Interdiscip Rev RNA 8:|
|Corley, Meredith; Solem, Amanda; Phillips, Gabriela et al. (2017) An RNA structure-mediated, posttranscriptional model of human ?-1-antitrypsin expression. Proc Natl Acad Sci U S A 114:E10244-E10253|
|Schulmeyer, Kayley H; Diaz, Manisha R; Bair, Thomas B et al. (2016) Primary and Secondary Sequence Structure Requirements for Recognition and Discrimination of Target RNAs by Pseudomonas aeruginosa RsmA and RsmF. J Bacteriol 198:2458-69|
|Corley, Meredith; Solem, Amanda; Qu, Kun et al. (2015) Detecting riboSNitches with RNA folding algorithms: a genome-wide benchmark. Nucleic Acids Res 43:1859-68|
|Kutchko, Katrina M; Sanders, Wes; Ziehr, Ben et al. (2015) Multiple conformations are a conserved and regulatory feature of the RB1 5' UTR. RNA 21:1274-85|
Showing the most recent 10 out of 22 publications