It was traditionally thought that the transcriptome would be mostly comprised of mRNAs, however advances in high-throughput RNA sequencing technologies have revealed the complexity of our genome. Non-coding RNA is now known to make up the majority of transcribed RNAs and in addition to those that carry out well-known housekeeping functions (e.g. tRNA, rRNA etc), many different types of regulatory RNAs have been and continue to be discovered. Many of these non-coding RNAs are thought to have a wide range of functions in cellular and developmental processes.
Long noncoding RNAs (lncRNAs) are a large and diverse class of transcribed RNA molecules with a length of more than 200 nucleotides that do not encode proteins. Their expression is developmentally regulated and lncRNAs can be tissue- and cell-type specific. A significant proportion of lncRNAs are located exclusively in the nucleus. They are comprised of many types of transcripts that can structurally resemble mRNAs, and are sometimes transcribed as whole or partial antisense transcripts to coding genes. LncRNAs are thought to carry out important regulatory functions, adding yet another layer of complexity to our understanding of genomic regulation.
Functions of lncRNA
LncRNAs may exert their functions… either by binding to DNA or RNA in a sequence specific manner or by binding to proteins. Some lncRNAs are actually precursors for smaller regulatory RNAs such as microRNAs or piwi RNAs. As opposed to microRNA, lncRNAs are not defined by a common mode of action, and can apparently regulate gene expression and protein synthesis in a number of different ways (Figure 1). A few lncRNAs have had their functions experimentally defined and so far they have been shown to be involved in fundamental processes of gene regulation including chromatin modification and structure as well as direct transcriptional regulation. Gene regulation may occur in cis (e.g. in close proximity to the transcribed lncRNA) or in trans (at a distance from the transcription site). Post-transcriptional functions of lncRNA include regulating RNA processing events such as splicing, editing, localization, translation and degradation.
It has recently been attempted to categorize the various types of molecular mechanisms that may be involved in lncRNA function. LncRNAs may be defined as one or more of the following four archetypes:
- The Signal archetype: functions as a molecular signal or indicator of transcriptional activity.
- The Decoy archetype: binds to and titrates away other regulatory RNAs or proteins.
- The Guide archetype: directs the localization of ribonucleoprotein complexes to specific targets.
- The Scaffold archetype: has a structural role as platform upon which relevant molecular components (proteins and or RNA) can be assembled.
lncRNA and disease
With such a wide range of functions, it is not surprising that lncRNA play a role in the development and pathophysiology of disease. LncRNAs have been found to be differentially expressed in various types of cancer including leukemia, breast cancer, hepatocellular carcinoma, colon cancer, and prostate cancer. Other diseases where lncRNAs are dysregulated include cardiovascular diseases, neurological disorders and immune-mediated diseases.
Only a relatively small proportion of lncRNAs have so far been investigated and although we can start to classify different types of lncRNA functions, we are still far from being able to predict the function of new lncRNAs. This is mainly due to the fact that unlike protein-coding genes whose sequence motifs are indicative of their function, neither lncRNA sequences nor their secondary structures are usually conserved and they don’t tend to contain conserved motifs. Other differences between lncRNA and mRNA are summarized in Table 1. The main challenges of working with lncRNA are the fact that they can be present in very low amounts, can overlap with coding transcripts on both strands and are often restricted to the nucleus.
Therefore there is an immediate need for sensitive and specific tools to investigate both the exact expression patterns and subcellular localization of lncRNAs as well as a range of tools to investigate the different types of function.
|Tissue-specific expression||Tissue-specific expression|
|Form secondary structure||Form secondary structure|
|Undergo post-transcriptional processing, i.e. 5’cap, polyadenylation, splicing||Undergo post-transcriptional processing, i.e. 5’cap, polyadenylation, splicing|
|Important roles in dieases and development||Important roles in diseases and development|
|Protein coding transcript||Non-protein coding, regulatory functions|
|Well conserved between species||Poorly conserved between species|
|Present in both nucleus and cytoplasm||Predominantly in nucleus|
|Total 20-24,000 mRNAs||Predicted 3-100 fold of mRNA in number|
|Expression level: low to high||Expression level: very low to moderate|
Similarities (gray) and differences (cyan) between mRNA and lncRNA