Determination of RNA structural diversity and its role in HIV-1 RNA splicing

Phillip J. Tomezsko, Vincent D. A. Corbin, Paromita Gupta, Harish Swaminathan, Margalit Glasgow, Sitara Persad, Matthew D. Edwards, Lachlan Mcintosh, Anthony T. Papenfuss, Ann Emery, Ronald Swanstrom, Trinity Zang, Tammy C. T. Lan, Paul Bieniasz, Daniel R. Kuritzkes, Athe Tsibris and Silvi Rouskin ()
Additional contact information
Phillip J. Tomezsko: Whitehead Institute for Biomedical Research
Vincent D. A. Corbin: Walter and Eliza Hall Institute
Paromita Gupta: Whitehead Institute for Biomedical Research
Harish Swaminathan: Whitehead Institute for Biomedical Research
Margalit Glasgow: Whitehead Institute for Biomedical Research
Sitara Persad: Whitehead Institute for Biomedical Research
Matthew D. Edwards: Massachusetts Institute of Technology
Lachlan Mcintosh: Walter and Eliza Hall Institute
Anthony T. Papenfuss: Walter and Eliza Hall Institute
Ann Emery: University of North Carolina at Chapel Hill
Ronald Swanstrom: University of North Carolina at Chapel Hill
Trinity Zang: The Rockefeller University
Tammy C. T. Lan: Whitehead Institute for Biomedical Research
Paul Bieniasz: The Rockefeller University
Daniel R. Kuritzkes: Brigham and Women’s Hospital
Athe Tsibris: Brigham and Women’s Hospital
Silvi Rouskin: Whitehead Institute for Biomedical Research

Nature, 2020, vol. 582, issue 7812, 438-442

Abstract: Abstract Human immunodeficiency virus 1 (HIV-1) is a retrovirus with a ten-kilobase single-stranded RNA genome. HIV-1 must express all of its gene products from a single primary transcript, which undergoes alternative splicing to produce diverse protein products that include structural proteins and regulatory factors1,2. Despite the critical role of alternative splicing, the mechanisms that drive the choice of splice site are poorly understood. Synonymous RNA mutations that lead to severe defects in splicing and viral replication indicate the presence of unknown cis-regulatory elements3. Here we use dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) to investigate the structure of HIV-1 RNA in cells, and develop an algorithm that we name ‘detection of RNA folding ensembles using expectation–maximization’ (DREEM), which reveals the alternative conformations that are assumed by the same RNA sequence. Contrary to previous models that have analysed population averages4, our results reveal heterogeneous regions of RNA structure across the entire HIV-1 genome. In addition to confirming that in vitro characterized5 alternative structures for the HIV-1 Rev responsive element also exist in cells, we discover alternative conformations at critical splice sites that influence the ratio of transcript isoforms. Our simultaneous measurement of splicing and intracellular RNA structure provides evidence for the long-standing hypothesis6–8 that heterogeneity in RNA conformation regulates splice-site use and viral gene expression.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2253-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:582:y:2020:i:7812:d:10.1038_s41586-020-2253-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2253-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().