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Canonical Mrna Is the Exception, Rather Than the Rule Jun-An Chen1 and Simon Conn2*

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Canonical Mrna Is the Exception, Rather Than the Rule Jun-An Chen1 and Simon Conn2* Chen and Conn Genome Biology (2017) 18:133 DOI 10.1186/s13059-017-1268-1 MEETING REPORT Open Access Canonical mRNA is the exception, rather than the rule Jun-An Chen1 and Simon Conn2* covering a breadth of small and long non-coding RNA Abstract species from yeast, Drosophila, plants and mammals, even A report on the Second Aegean International Conference presenting the therapeutic potential of these molecules in on the Long and the Short of Non-Coding RNAs, held various diseases. Plenary talks were further complemented in Heraklion, Greece, 9–14 June 2017. by active poster sessions, where participants engaged with more than 85 poster presenters during conference breaks. Keywords: Non-coding RNA, Review, Circular RNA, In this report, we briefly recount the conference con- lncRNA, miRNA tent by providing condensed, headline-style summaries of the research described in the talks and some of the Introduction posters. Within the scope of this brief report we have Investigations into gene regulation and disease patho- highlighted three key research themes: non-coding genesis have been protein-centric for decades. However, RNAs in disease; circular RNAs and their formation and in recent years there has been a profound expansion function; and RNA stability. However, we cannot pos- in our knowledge of the variety and complexity of sibly do justice to the quality and quantity of all work eukaryotic RNA species, particularly the non-coding presented. We would like to stress that omissions from RNA families. Vast amounts of RNA sequencing data this report are not based on quality, but simply a per- generated from various library preparation methods sonal judgement as to which material could be most have revealed these non-coding RNA species to be un- coherently presented within limited space. equivocally more abundant than canonical mRNA spe- cies. Furthermore, insight into the diverse mechanisms Non-coding RNAs in disease and functional roles of these RNA transcripts is emerging, pointing to their roles in maintaining cellular homeostasis Perhaps the most pivotal discovery regarding non- and gene regulation and/or directing various pathologies. coding RNAs are that they are not simply transcriptional The Second Aegean International Conference on the by-products, or splicing artefacts, but comprise a diverse population of actively synthesised and regulated RNA Long and the Short of Non-Coding RNAs focused on — — the key contemporary findings in this field. Organised transcripts. These transcripts can and do function by a scientific committee comprising Judy Lieberman within the contexts of cellular homeostasis and human (Harvard Medical School, Boston, USA), Zissimos pathogenesis. Technologies based on next-generation Mourelatos (University of Pennsylvania, Philadelphia, sequencing have revealed many novel classes of non- USA) and Andrei Thomas-Tikhonenko (The Children's coding RNA transcripts, but biochemical characterisa- Hospital of Philadelphia, Philadelphia, USA), the con- tion to ascribe the mechanisms behind their functions, ference was held at the Aldemar Knossos Royal Village especially in vivo, provides an essential roadmap to guide Conference Center in Heraklion, Crete (Greece), 9–14 the research field. Two overriding questions remain to June 2017, and was attended by 125 delegates from nu- be answered: 1) how is long non-coding RNA (lncRNA) merous countries. There were no defined keynote talks, targeted to the genome, and 2) are lncRNAs functionally but 25 invited talks and 15 short contributed talks, important? Ingrid Grummt (German Cancer Research Center, Heidelberg, Germany) elegantly demonstrated that an * Correspondence: [email protected] E2F1-regulated antisense lncRNA named Khps1 acti- 2Centre for Cancer Biology, an alliance between SA Pathology and University of South Australia, Adelaide, SA 5000, Australia vates expression of its cognate mRNA, SPHK1 (sphingo- Full list of author information is available at the end of the article sine kinase 1). This is achieved through forming a © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen and Conn Genome Biology (2017) 18:133 Page 2 of 4 DNA–RNA triplex that recruits histone acetyltransfer- oncogene (MITF)-related lncRNA, SAMMSON. They ase p300/CBP and other associated effector proteins to demonstrated that the “addiction of melanoma” to this the gene promoter. By developing a biochemical purifi- lncRNA is mediated through its interaction with distinct cation method for DNA–RNA triplexes as an alterna- proteins, with contrasting functions, to regulate melan- tive to ChiRP-seq (chromatin isolation by RNA oma progression. This finding prompts an interesting purification), the Grummt group proposed a hotly de- hypothesis that lncRNA might function as a molecular bated model that these triplexes might be a general switch to rewire RNA binding proteins in cancer. characteristic of target gene recognition by chromatin- Multiple high-profile presenters, including David Bartel interacting lncRNAs. While genome-wide binding sites (Massachusetts Institute of Technology, Cambridge, USA) for MEG3 lncRNA supported this new model, Jun-An and David Corey (UT Southwestern Medical Center, Chen’s group (Academia Sinica, Taipei, Taiwan) found Dallas, USA), thematically questioned whether ncRNA the same lncRNA to be highly expressed in motor neu- copy numbers were sufficiently abundant to co-regulate rons, following systematic profiling studies on embry- target molecules (whether protein, RNA or DNA) in a onic motor neuron-enriched lncRNAs. Loss of Meg3 physiological context. Corey further encouraged all at- directs motor neuron subtype identity by regulating the tendees to assess absolute abundance of focal ncRNA epigenetic landscape through PRC2, resulting in altered and their target(s) and also their subcellular localisation— expression of homeotic genes and homeotic transform- an approach that contributed greatly to his own study on ation in knockout mice. Martin Crespi (Institute of factors involved in Argonaute-mediated nuclear RNAi. Plant Sciences Paris-Saclay, Paris, France) reported an- Quantifying the stoichiometric relationships between other homeotic transformation effect for a lncRNA in ncRNAs and their targets will likely be necessary in future Arabidopsis, whereby broad modulation of alternative research reports. splicing resulted in altered root branching. Together, these reports endorse lncRNAs as having a function in Circular RNAs: formation and function homeotic transformation. As “new kids on the block” in the non-coding RNA Iannis Aifantis (NYU Langone Medical Center, New family, the circular RNAs (circRNAs) are a large group York City, USA) performed a genome-wide lncRNA of uniquely alternatively spliced RNA molecules, which reverse-genetics screen with an enhanced Cas9 repres- are ubiquitous among eukaryotes and are proving func- sor protein to investigate regulation of key targets tional in a plethora of contexts. Historically much mal- downstream of Myc. He identified a conserved lncRNA igned because of their relatively low abundance and that coordinated chromosome conformation (three-di- high diversity, it may be surprising that five individuals’ mensional DNA looping) in T-cell acute lymphoblastic presentations focused predominantly or exclusively on leukaemia, with knockdown studies reducing tumours discrete aspects of circRNA biogenesis, recognition and in vivo. regulation. Some presented on circRNA functions hitherto These systematic analyses were also employed by other unheard-of for any ncRNA. researchers at the meeting, including Andrea Ventura Mariangela Morlando (Universita di Roma, Rome, Italy) (Memorial Sloan Kettering Cancer Center, New York, showed that, while not widespread, certain circRNAs USA), whose talk “Cancer Modeling in the CRISPR Age” are not strictly non-coding RNAs at all. An example be- reaffirmed this approach as the gold-standard for genetic ing circ-ZNF609, these circRNAs retain endogenous in- screens in cell lines and model organisms alike. Joshua ternal ribosome entry sites from the cognate mRNA, Mendell (UT Southwestern Medical Center, Dallas, which enables their translation into protein. She also USA) reported on a Cas9 genome-wide loss-of-function identified a new circRNA biogenesis factor, FUS, whose screen to identify new regulators of the microRNA pathogenic mutations in amyotrophic lateral sclerosis (miRNA) pathway. This screen revealed a novel phos- and autism are linked to altered circRNA formation. phorylation and dephosphorylation cycle for Argonaute Gregory Goodall (Centre for Cancer Biology, Adelaide, 2 (AGO2), which is stimulated by regulated interactions Australia) reported on the role of Quaking, an RNA between miRNA and targets to maintain the global effi- binding protein that regulates circRNA biogenesis in ciency of miRNA-mediated silencing. Collaborative dis- epithelial–mesenchymal transition, a model of cancer tribution of the outcomes of these CRISPR screens
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