An introduction to this FEBS Letters Special Issue, edited by Andre Gerber, Michaela Zavolan and Wilhelm Just, is provided below by the issue's editorial [Zavolan. M. and Gerber, A.P. (2018) Mirroring the multifaceted role of RNA and its partners in gene expression. FEBS Lett 592, 2825–2827]
In the early years of Molecular Biology, the role of RNA was largely considered to be the transmission of the genetic information stored in the DNA into polypeptides. Three major types of RNA engaged in these processes were known: messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA). However, within the last half century our knowledge about RNA classes, abundance and diversity of functions has increased dramatically. The discovery that the ribosome is essentially a ribozyme 1, 2 especially brought the central role of RNA for cellular life into the spotlight. The turn of the millennium was also the time of another far‐reaching realization, that of the pervasiveness of small RNA‐dependent regulation of gene expression 3. Within the decade that followed, RNAs were found in essentially all regulatory layers of gene expression, from the epigenetic layer at the top of the gene expression cascade 4, 5 to the most distal translation layer 6. Much of this rapid transition was enabled by sequencing technologies that were developed in the wake of the human genome project. Coupled with ingenious protocols for isolating RNAs of various sizes and molecular properties (e.g. 7) and computational methods to annotate various classes of small RNAs 8, the set of regulatory RNAs has expanded and diversified rapidly. We now know that < 2% of the human genome contains protein‐coding genes, whereas 80% is transcribed into noncoding RNAs (ncRNAs), classified based on their size into small and long noncoding RNAs (lncRNAs). Small ncRNAs include the highly investigated microRNAs (miRNAs) that were found to be increased in various cancer types where they exhibit pro‐oncogenic activity 9. LncRNAs are long (> 200 nucleotides) transcripts that functionally contribute to the control of cell differentiation and maintenance of cell identity. Notably, as most (~ 90%) of disease‐associated single nucleotide polymorphisms are located in gene regulatory or intergenic regions, long‐intergenic ncRNAs (lincRNAs) in particular may have pivotal impact for the development of personalized medicine therapies in the future10. Whether small or long, ncRNAs often bear domains enabling direct and specific interactions with other RNAs, forming RNA‐RNA hybrids that participate in the control of gene expression and biogenesis of RNAs 11.
Also known since the early days of Molecular Biology is that RNA is never “naked” in cells but covered by a host of proteins. Therefore, the discovery of new types of RNA molecules went hand in hand with the unearthing of new RNA‐binding proteins that specifically or promiscuously interact with RNAs to implement various functions. In this respect, FEBS Letters published recently a series of review articles related to RNA‐binding proteins and their cellular and neuronal functions (FOCUS ON… mRNA transport, local translation and processing) 12-17. The present Special Issue extends this series by highlighting recent topics in RNA research such as RNA modifications, RNA‐RNA and RNA‐protein interactions, and RNA‐regulated pathways. These exemplify the steadily increasing complexity and intertwined nature of RNA function and regulation in biology.
While Ivanov and colleagues 18 outline current knowledge on how RNA modifications regulate the fate and generation of tRNA fragments, Kuckles and Buehler 19 refer to the increasingly recognized role of RNA modifications in mRNA, discussing adenosine methylation and its function in mRNA metabolism. Furthermore, Shevchenko and Morris 20 focus on another prominent RNA modification found in mRNAs as well as in tRNAs, by reviewing the latest developments in adenosine to inosine editing and its significance in regulating gene expression by means of the ADAR protein family.
A revealing article by Ulitsky 21 discusses the known types of interactions between short (miRNAs) and long (lncRNAs) RNAs, illustrating how these molecules can regulate each other and eventually impact gene expression of downstream targets. Lekka and Hall 22 emphasize the wide‐scale involvement of miRNAs and lncRNAs in the pathophysiology, focusing on cancer, cardiovascular and neurological disorders.
RNA‐protein interactions are discussed by Zagrovic et al. 23, Albihlal and Gerber 24 and Gallagher and Ramos 25. These articles focus respectively, on computational work of the universal genetic code and the binding specificity of nucleobases and amino acids; on recent proteomic approaches that revealed many “unconventional” RNA‐binding proteins lacking characteristic RNA‐binding domains (e.g. metabolic enzymes); and on structural features for the regulation of local mRNA translation in neurons by RNA‐binding proteins. Additionally Winata and Korzh 26 summarize the current knowledge on maternal mRNA regulation, with particular focus on cytoplasmic polyadenylation as a mechanism for translational regulation.
The remaining Reviews focus on the dynamics of RNA and interacting proteins within the cell. Lecuyer and colleagues 27 discuss the current knowledge on intracellular RNA localization and its physiological implications. Pong and Gullerova 28 highlight noncanonical roles of proteins of the RNA interference pathway, Drosha, DGCR8, Dicer and Ago, and Dvinge 29 provides another fascinating example of the increased complexity in gene regulation, explaining how multiple gene regulatory layers are coupled to core components of the spliceosome, thereby performing regulatory functions in splicing.
The editors of this Special Issue and the FEBS Letters editorial team very much hope that this issue will fill a gap in the landscape of RNA biology by providing cutting edge overviews on the topic as well as new ideas on how the field may develop in the future.
1 Nissen P, Hansen J, Ban N, Moore PB and Steitz TA(2000) The structural basis of ribosome activity inpeptide bond synthesis. Science 289, 920–930.
2 Cech TR (2000) The ribosome is a ribozyme. Science 289, 878–879.
3 Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P et al. (2000) Conservation of the sequence
and temporal expression of let-7 heterochronic regulatory RNA. Nature 408,86–89.
4 Verdel A, Jia S, Gerber S, Sugiyama T, Gygi S, Grewal SIS and Moazed D (2004) RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303,672–676.
5 Aravin A, Gaidatzis D, Pfeffer S, Lagos-Quintana M, Landgraf P, Iovino N, Morris P, Brownstein MJ, Kuramochi-Miyagawa S, Nakano T et al. (2006) A novel class of small RNAs bind to MILI protein in mouse testes. Nature 442, 203–207.
6 Ivanov P, Emara MM, Villen J, Gygi SP and Anderson P (2011) Angiogenin-induced tRNA fragments inhibit translation initiation. Mol Cell 43, 613–623.
7 Hafner M, Landgraf P, Ludwig J, Rice A, Ojo T, Lin C, Holoch D, Lim C and Tuschl T (2008) Identiﬁcation of microRNAs and other small regulatory RNAs using cDNA library sequencing. Methods 44,3–12.
8 Will S, Reiche K, Hofacker IL, Stadler PF and Backofen R (2007) Inferring noncoding RNA families and classes by means of genome-scale structure-based clustering. PLoS Comput Biol 3, e65.
9 Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA et al. (2005) MicroRNA expression proﬁles classify human cancers. Nature 435, 834–838.
10 Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A and Rinn JL (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and speciﬁc subclasses. Genes Dev 25,1915–1927.
11 Guil S and Esteller M (2015) RNA-RNA interactions in gene regulation: the coding and noncoding players. Trends Biochem Sci 40, 248–256.
12 Fernandez-Moya SM, Ehses J and Kiebler MA (2017) The alternative life of RNA-sequencing meets single molecule approaches. FEBS Lett 591, 1455–1470.
13 Moschall R, Gaik M and Medenbach J (2017) Promiscuity in post-transcriptional control of gene expression: Drosophila sex-lethal and its regulatory partnerships. FEBS Lett 591, 1471–1488.
14 Ederle H and Dormann D (2017) TDP-43 and FUS en route from the nucleus to the cytoplasm. FEBS Lett 591, 1489– 1507.
15 Donlin-Asp PG, Rossoll W and Bassell GJ (2017) Spatially and temporally regulating translation via mRNA-binding proteins in cellular and neuronal function. FEBS Lett 591, 1508–1525.
16 Pilaz L-J and Silver DL (2017) Moving messages in the developing brain - emerging roles for mRNA transport and local translation in neural stem cells. FEBS Lett 591, 1526– 1539.
17 Raab-Graham KF and Niere F (2017) mTOR referees memory and disease through mRNA repression and competition. FEBS Lett 591, 1540–1554.
18 Lyons SM, Fay MM and Ivanov P (2018) The role of RNA modiﬁcations in the regulation of tRNA cleavage. FEBS Lett 592, 2828–2844.
19 Knuckles P and Buehler M (2018) Adenosine methylation as a molecular imprint deﬁning the fate of RNA. FEBS Lett 592, 2845–2859.
20 Shevchenko G and Morris KV (2018) All I’s on the RADAR: role of ADAR in gene regulation. FEBS Lett 592, 2860– 2873.
21 Ulitsky I (2018) Interactions between short and long noncoding RNAs. FEBS Lett 592, 2874–2883.
22 Lekka E and Hall J (2018) Non-coding RNAs in disease. FEBS Lett 592, 2884–2900.
23 Zagrovic B, Bartonek L and Polyansky AA (2018) RNA-protein interactions in an unstructured context. FEBS Lett 592, 2901–2916.
24 Albihlal WS and Gerber AP (2018) Unconventional RNA-binding proteins: an uncharted zone in RNA biology. FEBS Lett 592, 2917–2931.
25 Gallagher C and Ramos A (2018) Joining the dots: protein‐RNA interactions mediating local mRNA translation in neurons. FEBS Lett 592, 2932–2947.
26 Winata CL and Korzh V (2018) The translational regulation of maternal mRNAs in time and space. FEBS Lett 592, 3007–3023.
27 Bovaird S, Patel D, Padilla J‐CA and Lecuyer E (2018) Biological functions, regulatory mechanisms and disease relevance of RNA localization pathways. FEBS Lett 592, 2948–2972.
28 Pong SK and Gullerova M (2018) Non‐canonical functions of microRNA pathway enzymes — Drosha, DGCR8, Dicer and Ago proteins. FEBS Lett 592, 2973–2986.
29 Dvinge H (2018) Regulation of alternative mRNA splicing: old players and new perspectives. FEBS Lett 592, 2987–3006.