A new class of RNAs has recently emerged as a key player in many rapidly growing areas of research, including epigenetics, hormone signaling, development, stem cell biology, cancer, brain function and plant biology.1–9 The growth of this area has been fueled by recent advances in sequencing technology. These RNAs (long non-coding RNAs, or lncRNAs) are typically 1,000–10,000 residues in length. LncRNAs are often polyadenylated, transcribed by RNA polymerase II and spliced.3,6,7,10–13 While some lncRNAs are found in the cytoplasm, most are localized in the nucleus. Many lncRNAs are associated with histone methylation, chromatin remodeling and subsequent epigenetic effects.14 In the field of epigenetics, the mechanism by which epigenetic factors find their targets remains largely a mystery. The importance of lncRNAs has been underscored in the context of mammalian genomes, where recent evidence suggests that lncRNAs may provide a missing epigenetic link between DNA, histones and methylation factors.15
In humans, over 70% of the genome is actively transcribed.16 In contrast, protein-coding genes constitute only 1–2% of the genome.17 The active transcription of non-protein coding genes gives rise mainly (80–90%) to lncRNAs.18 While some lncRNAs, such as MALAT1, are highly abundant transcripts, many lncRNAs do show low count. However, low transcription levels do not necessarily reflect lack of functionality. Studies on the stability of lncRNAs19 have shown that lncRNAs have stabilities comparable to those of mRNAs (albeit slightly less on average). Here, time scales range from 30 min up to 16 h in the case of MALAT1. Protein half-lives range from 30 min to 2 h.20 We note that transcription rates range from 1–50 kb/min.21 From these data, a picture of the nucleus emerges, where lncRNAs are synthesized in minutes and may persist for hours.
Long noncoding RNAs (lncRNAs) are very broadly defined by two major characteristics: (1) length of the transcript (> 200 nts) and (2) having little or no potential for translation.22 Some lncRNAs ('macroRNAs') achieve incredible lengths, extending beyond 90 kB. Examples include the 108 kB Air and the 91 kB kcnq1ot1.23–25 The term lncRNA is traditionally reserved for regulatory RNAs. LncRNAs are often further divided into categories based on their relative position to neighboring protein-coding genes. Natural antisense transcripts (NATs) are transcribed from the antisense strand of protein-coding genes, overlapping at least one exon. Large intervening noncoding RNAs, as known as long intergenic noncoding RNAs (lincRNAs), are positioned far from protein-coding genes. Intronic noncoding RNAs are uniquely transcribed from intron regions of protein-coding genes either in the sense or antisense direction. Bidirectional lncRNAs are transcribed in the antisense direction in the region of the promoter of a protein-coding gene. An exact estimation of the number of lncRNAs is quite challenging due to their cell-specific, tissue-specific, developmental stage specific and disease-specific expression profiles. The most recent estimates place the number of lncRNAs in humans at ~15,000.26 However, tens of thousands of lncRNAs have been profiled this year alone.27–30
In terms of function, nascent paradigms of lncRNA action include, but are not limited to, critical regulatory roles in embryonic stem cell pluripotency,31 brain function,32–34 subcellular compartmentalization35,36 and chromatin remodeling.3,8,37 Many have been linked to various diseases, such as cancer.38 We note that lncRNAs play key roles in intracellular and extracellular signaling (SRA, Gas5, LINoCR, BC1, BORG and NRON) and stress response (e.g., SAT III, PRINS, npc536, hsr omega transcript, gadd7, Hsr1 and bace1as). More detailed discussion of functional aspects of lncRNAs can be found in several excellent recent review articles.39 Due to the large sizes of intact lncRNAs relative to typical biophysical systems, very few structural studies of these RNAs have been performed.40 By comparison, the high-resolution 3-D structure of the intact ribosome (~5 kB in total) required ~25 y for its solution.41,42
For lncRNAs, the following questions remain unanswered: (1) Are lncRNAs highly structured or disordered? (2) Do they contain globular sub-domains, or are they organized linearly in chains of stem-loops? (3) Do lncRNAs exist in ribonucleoprotein complexes or as isolated RNAs that transiently interact with proteins? (4) Do these molecules contain a compact core, or are they more extended?
Mechanistic studies of lncRNAs have the potential to be more challenging than ribosomes, because lncRNAs are not as highly conserved nor as highly expressed. Nonetheless, RNA molecules are well known to utilize a wide spectrum of functional elements either at their sequence, secondary or tertiary level. RNA interference and RNA silencing leverage sequence specificity to control gene expression. Riboswitch RNAs regulate gene expression via secondary structure. The ribosome uses its complex tertiary structure to synthesize proteins, in a manner analogous to a protein-based molecular machine. LncRNAs may or may not use aspects of each of these three mechanisms to regulate gene expression. In light of the tremendous variety of lncRNAs, it is possible that all three of these mechanisms are employed by lncRNA systems. A great deal of useful information can be produced using modern structural biology techniques In this review, we provide a summary of current knowledge of sequence and structural features of eukaryotic lncRNAs. Although studies of lncRNA tertiary structure have yet to be performed, we examine known crystallographic structures of other RNAs and explore the possibilities that might occur in lncRNA systems.
lncRNAs are not likely to exist in ribosome-like ribonucleoprotein complexes
As the ribosome is the only RNA structure > 1 kB solved to date, we ask the question, are lncRNA systems similar to ribosomes in their structural composition? We note that our recent structural study of the SRA lncRNA revealed RNA secondary structure similar to the ribosome in its overall architecture. This study, which used multiple forms of extensive chemical probing combined with multiple sequence analysis, demonstrated that SRA has 4 sub-domains with numbers of helices and loops comparable (in proportional terms) to a ribosome subunit. We currently have no information on the tertiary structure of this lncRNA or other lncRNAs. In addition, we do not know if lncRNAs exist in ribonucleoprotein complexes (RNPs) or as isolated RNAs.
To compare with the ribosome, we note that it consists of a few long RNAs complexed with many unique (i.e., non-identical) proteins. The total number of protein-coding genes in the human genome is estimated to be ~21,000.72 As most proteins reside in the cytoplasm, we can reasonably estimate that the number of proteins in the nucleus, Nprotein, nucl < 21,000. Many thousands of lncRNAs have been identified, with most residing in the nucleus. As a very conservative estimate, we use NlncRNA, nucl > 3,000, giving NlncRNA,nucl/Nprotein,nucl > 1/7. We note that many lncRNAs are as large as or larger than the ribosome. In the case of the ribosome itself, the ratio of RNA molecules to protein molecules is NrRNA/Nrp ~1/25 for each subunit. Thus, even if every single unique protein encoded in the human genome formed a complex with a lncRNA, we would still not expect lncRNAs to be similar in structural composition to ribosomes. There are not enough unique proteins to form ribosome-like complexes (with ~25 unique proteins) for each lncRNA. Using an optimistic estimate that 1 in 10 of all proteins binds to a lncRNA, this would still provide less than 1 unique protein per lncRNA. Therefore, we conclude that lncRNAs in the nucleus are not likely to exist in ribosome-like RNP complexes. A few lncRNAs could theoretically exist in ribosome-like complexes. These complexes would be more likely to exist in the cytoplasm. The following possibilities remain: (1) lncRNAs exist in RNP complexes with many repeats of a few proteins, (2) lncRNAs exist in complexes with only a few proteins or (3) lncRNAs exist as isolated RNAs that transiently bind proteins as needed for function. We note that in the case of (1), to produce a similar protein density (number of proteins per RNA) to ribosomes, we would require ~10 proteins bound per 1 kB of lncRNA (e.g., 90 identical proteins bound to MALAT-1). While (1) is certainly possible, we favor (2) or (3).
The large diversity of lncRNAs may produce complexes similar in overall form to telomerase RNA, RNase P or the group I and II introns
While we suspect lncRNA complexes are not similar to ribosomes, we cannot rule out similarity to RNase P, telomerase RNA or the group I and group II introns. In the case of an ‘RNase P-like’ complex, the lncRNA would be highly structured and compact, containing a main protein binding site, where various proteins bind (Fig. 3A). Alternatively, the lncRNA could be decentralized without a compact core. It may contain several distinct protein-binding sites and act as flexible structural tether, as suggested for the telomerase RNA (Fig. 3B).64 The lncRNA could also be a stand alone, highly structured RNA, similar to the group I and group II introns. In this case, the lncRNA may transiently bind proteins as needed. Finally, another possibility is a highly disordered RNA, containing loosely organized protein binding domains (Fig. 3C). Our experimentally determined secondary structure of SRA is highly organized and more suggestive of a structure with characteristics of Figure 3A. We enumerate various combinations of secondary structure and tertiary structure in Table 1, with column 1 corresponding to Figure 3A, column 6 corresponding to Figure 3B, and columns 6–7 possibly corresponding to Figure 3C.
Figure 3. Possibilities for lncRNA three-dimensional architecture. These homology models represent concepts for possible lncRNA 3D structures. (A) lncRNA (pink) contains a compact tertiary core. The lncRNA may have a main protein (green) binding site, responsible for binding various protein factors. (B) De-centralized scaffold. In this scenario, the lncRNA does not have a compact core. The lncRNA may have several protein (yellow) binding sites. (C) Loosely organized protein binding domain with regions of unstructured RNA. The lncRNA may contain several long stretches of disordered single stranded RNA.
Table 1. Possibilities for structural configurations of lncRNAs
|Core secondary structure?
|Binding domain secondary structure?
|Core tertiary structure?
|Binding domain tertiary structure?
Columns 1–8 represent different RNA structural configurations. Column 1 represents a highly structured configuration similar to the ribosome. Column 8 represents an unstructured RNA. Columns 2–7 represent various intermediate cases. Columns 6–8 represent a decentralized structural configuration. Our recent study demonstrates that the entire SRA lncRNA has well-organized secondary structure, corresponding to columns 1–3, depending on the degree of tertiary structure. All cases may also include single-stranded regions that organized upon protein binding.
Possibilities for structure-based mechanisms of lncRNAs
Although many more proteins have been studied in mechanistic detail relative to RNAs, a diverse portfolio of RNA mechanisms has emerged, based on either sequence, secondary or tertiary organization of RNA molecules, as well as combinations of these mechanisms. In sequence-based mechanisms, such as RNA interference by siRNAs and RNA silencing by miRNAs, the RNA plays a very minor structural role. Here, the role of RNA is mainly to add sequence specificity to the process, allowing the RISC complex to find its target and trigger a largely protein-based regulation mechanism.73,74
Over the past decade, a new mechanism of regulation has emerged, which is almost entirely based on RNA secondary structure.75–80 In riboswitch RNA systems, two secondary structures compete with each other to control termination of transcription (some riboswitch RNAs also control translation by sequestering the start codon). Here, one sequence in the 5′-UTR of the mRNA codes for two different secondary structures. The presence or absence of a metabolite selects one of the two structures, switching gene expression on or off. For example, in the case of the SAM-I riboswitch, the presence of a metabolite (SAM) causes the RNA to fold into a compact aptamer, favoring formation of the transcriptional terminator helix, turning gene expression of SAM synthetase off. In the absence of the metabolite, a second, alternative helix is formed, preventing formation of the transcriptional terminator helix, turning gene expression on. Riboswitches are more ‘secondary structure specific’ than ‘sequence specific’, often mandating stochastic context-free grammar algorithms for searches, as opposed more conventional BLAST-like searches. Interestingly, artificial riboswitch-like systems were first designed and produced in the lab and only later discovered in bacteria.81
RNA mechanisms based on tertiary structure are often allosteric and may be described by ‘induced-fit’ or ‘conformational selection’.78,82,83 In induced-fit, an event, such as protein- or ligand-binding, triggers a large conformational change. In conformational selection, the system is often frustrated between two conformations. A protein- or ligand-binding event shifts the equilibrium to one of the two conformations. In the case of the ribosome, many conformational fluctuations occur simultaneously and at different time scales. Protein binding or GTP hydrolysis events act to synchronize the fluctuations, shifting the equilibrium to the next basin in the energy landscape, allowing the ribosome to progress through the elongation cycle.84–87
Time scales and order of events
In addition to the three-dimensional structure of lncRNAs, the order of events and kinetics of these systems is essential for mechanistic understanding. For example, crystallographic structures have been solved for many ribosome complexes; however, the mechanism of ribosome translocation is still not understood. Rapid kinetics studies88,89 define the overall order of events. Single-molecule studies help elucidate the mechanism for transitions between states.90 A fusion of structural and kinetic information is required to unlock mechanism. Interestingly, the overall order of events can often be obtained before high-resolution crystallographic structures are available.
To illustrate potential time scales involved in lncRNA mechanism, we consider the lncRNA DBE-T, a key component of the epigenetic switch associated with Facioscapulohumeral muscular dystrophy (FSHD).37 This lncRNA is a cis-acting tether that recruits the epigenetic factors D4Z4 and Ash1L to the D4Z4 binding element (DBE) on chromatin, driving histone methylation and 4q35 gene transcription. One possible order of events may be (Fig. 4): (A) transcription, (B) lncRNA folding, (C) epigenetic protein binding to the lncRNA, (D) epigenetic protein binding to the chromatin, and (F) action of the epigenetic protein (e.g., histone methylation). Each of these steps will have its own time scale. Identifying the rate-limiting step will yield significant insight into the mechanism of lncRNA action. Other scenarios are also possible, involving different orders of events and different combinations of steps. For other classes of lncRNAs, entirely different events may occur.
Figure 4. An example of potentially relevant time scales for lncRNA activity: DBE-T lncRNA. DBE-T is a cis-acting tether than recruits epigenetic factors to chromatin. Steps af each have an associated timescale, t. (A) Initial state. (B) Transcription of DBE-T. (C) DBE-T folding. (D) The epigenetic factor binds to the lncRNA. (E) The epigenetic factor binds to chromatin. (F) The epigenetic factor marks the chromatin (e.g., histone methylation).
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