Dissecting the function of cytoplasmic long non-coding RNAs during neuronal differentiation and disease

With the advent of deep sequencing technologies, such as RNA-Seq, regions of the genome previously described as "Junk DNA" are now understood to code for an extensive catalogue of short and long non-coding RNAs. ~48,000 transcripts are annotated as lncRNAs in the human genome (GENCODE). Long non-coding RNAs (LncRNAs) are defined as RNA transcripts >200nt long, but lack large open reading frames (>100 codons), and therefore were initially described as non-coding.

However, with the development of novel sequencing techniques and more sensitive pipelines for detection of small peptides, many lncRNA containing one or more small open reading frames (smORF) have been identified, along with their peptide products. This blurs the line between coding and non-coding RNA and adds another level of complexity to the role of lncRNAs.

While the catalogue of annotated lncRNAs is expanding rapidly, still relatively few transcripts have had their functions fully characterised and the majority of these are localised to the nucleus. Furthermore, studies have identified many cytoplasmic lncRNAs as having critical roles in a number of cellular processes from differentiation, stress responses and disease. Therefore there is a huge pool of potentially functional cytoplasmic lncRNAs that demand investigation.

In the brain ~40% of all lncRNAs are specifically expressed with many showing precise temporal and spatial expression. Previous studies have shown that lncRNAs play a crucial role in both the maintenance of stemness and regulating neuronal differentiation, at all stages. Poly-Ribo-Seq has revealed that lncRNAs dynamically interact with ribosomes during neuronal differentiation. This suggests a possible role for lncRNAs to influence differentiation at a translational level, by modulating translational machinery, mRNA availability, or potentially through production of biologically active micropeptides from smORFs. Additionally, many lncRNAs have been implemented as both protectors against, and drivers of, a range of CNS diseases including; glioma, Alzheimer's disease, neuropathic pain and Amyotrophic Lateral Sclerosis.


This project aims to build upon the current knowledge of cytoplasmic lncRNAs involved in neuronal differentiation by elucidating their mechanisms of action and characterising the coding potential of smORFs in lncRNAs. This will reveal the roles specific lncRNAs have in either maintaining stemness or driving differentiation. Once characterised, cytoplasmic lncRNAs that are biologically active in the brain could be further interrogated to identify potential roles in CNS diseases.