Published as a full article in Cell on Sep. 25th, 2014, a research team led by Prof. CHEN Ling-Ling, at Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences , Chinese Academy of Sciences(CAS), in collaboration with Prof. YANG Li, at CAS-MPG Partner Institute for Computational Biology (PICB), demonstrate the mechanism of circular RNA biogenesis and presents the generality of alternative circularization for the complexity of mammalian posttranscriptional regulation. This work is also highlighted by a “Leading Edge Preview” on the same issue in Cell by Quentin Vicens and Eric Westhof.
Exon circularization has been identified from many loci in mammals, but the detailed mechanism of its biogenesis has remained elusive. The authors take advantage of non-polyadenylated and RNase R treated RNA-seq from H9 human embryonic stem cells (hESCs) with a newly developed computational pipeline to predict back spliced junctions and systematically characterize circular RNAs.
Importantly, they have recapitulated circular RNA formation and offered multiple lines of evidence to support the conclusion that circular RNA formation is dependent on flanking complementary sequences, including either repetitive or non-repetitive elements. Strikingly, such sequences exhibit rapid evolutionary changes among mammals, showing that exon circularization is evolutionarily dynamic. Furthermore, they show that the exon circularization efficiency is regulated by the competition of RNA pairing by complementary sequences within individual introns or across flanking introns. Alternative formation of inverted repeated Alu pairs (IRAlus) and the competition between them lead to alternative circularization, resulting in multiple circular RNA transcripts produced from a single gene.
The identification of alternative circularization further expands our understanding of gene expression regulation. Through alternative splicing, multiple functional mRNAs (and proteins) could be produced from a single gene. These multiple functional mRNAs are generally thought to exist only as linearized molecules. This work shows that alternative circularization coupled with alternative splicing can produce a variety of additional circular RNAs from one gene. Collectively, exon circularization mediated by complementary sequences in human introns and the potential to generate alternative circularization products extend the complexity of mammalian posttranscriptional regulation.
This study entitled "Complementary Sequence-Mediated Exon Circularization" was published on Cell as a full article.
This work was supported by grants from Chinese Academy of Sciences, the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and Shanghai Institutes for Biological Sciences, CAS.
Figure legend: The competition models of RNA pairing by complementary sequence-mediated exon circularization. (Left) The RNA pairing by IRAlus within one individual intron (red arrows) promotes normal constitutive splicing (dash lines), resulting in a linearized RNA transcript with exon inclusion and no circularization. (Right) RNA pairing by IRAlus across flanking introns promotes back splicing, leading to a linearized RNA transcript with exon skipping and circularization. (Image provided by Prof. CHEN Lingling and Prof. YANG Li `s group)
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