Long non‐coding RNAs in development and disease: conservation to mechanisms

Abstract

Our genomes contain the blueprint of what makes us human and many indications as to why we develop disease. Until the last 10 years, most studies had focussed on protein-coding genes, more specifically DNA sequences coding for proteins. However, this represents less than 5% of our genomes. The other 95% is referred to as the 'dark matter' of our genomes, our understanding of which is extremely limited. Part of this 'dark matter' includes regions that give rise to RNAs that do not code for proteins. A subset of these non-coding RNAs are long non-coding RNAs (lncRNAs), which in particular are beginning to be dissected and their importance to human health revealed. To improve our understanding and treatment of disease it is vital that we understand the molecular and cellular function of lncRNAs, and how their misregulation can contribute to disease. It is not yet clear what proportion of lncRNAs is actually functional; conservation during evolution is being used to understand the biological importance of lncRNA. Here, we present key themes within the field of lncRNAs, emphasising the importance of their roles in both the nucleus and the cytoplasm of cells, as well as patterns in their modes of action. We discuss their potential functions in development and disease using examples where we have the greatest understanding. Finally, we emphasise why lncRNAs can serve as biomarkers and discuss their emerging potential for therapy.No conflicts of interest were declared. What are lncRNAs?LncRNAs are RNAs of >200 nucleotides (nt) in length that are not thought to code for proteins. Although our appreciation and understanding of lncRNA function and importance has exploded in the last decade, the first lncRNAs were discovered in the 1990s: BC200, H19 [1], and Xist [2]. In the post-genomic era, extensive and deep RNA-Seq has revealed the existence of huge numbers of novel RNA transcripts, including lncRNAs. Many of these novel transcripts are low in abundance and so were not previously identified. Several consortia have been responsible for sequencing RNA from a variety of tissues, cell types, organisms, and disease states, and we now have a much more precise view of which RNA transcripts are expressed, and when and where (GENCODE [3], GTEX [4], FANTOM [5]).

Non-Coding RNAs and Hereditary Hemorrhagic Telangiectasia

“…LncRNAs can be divided into two functional groups based on their sub-cellular localization: (1) nuclear and (2) cytoplasmic. Nuclear lncRNAs can influence gene expression via various mechanisms, including chromatin remodeling, protein sequestration and the enhancement or dampening of promoter activity [ 107 ]. One of the ways that cytoplasmic lncRNAs can influence gene expression is by regulating the availability and stability of miRs by acting as miR “sponges” [ 107 ].…”

“…Nuclear lncRNAs can influence gene expression via various mechanisms, including chromatin remodeling, protein sequestration and the enhancement or dampening of promoter activity [ 107 ]. One of the ways that cytoplasmic lncRNAs can influence gene expression is by regulating the availability and stability of miRs by acting as miR “sponges” [ 107 ]. Although lncRNA mechanisms have been well characterized, evidence suggests that most lncRNAs are non-functional [ 107 ].…”

“…One of the ways that cytoplasmic lncRNAs can influence gene expression is by regulating the availability and stability of miRs by acting as miR “sponges” [ 107 ]. Although lncRNA mechanisms have been well characterized, evidence suggests that most lncRNAs are non-functional [ 107 ]. Nonetheless, a few lncRNAs have been implicated in vascular and endothelial cell biology.…”

Identification and characteristics of postnatal development-related long non-coding RNAs under microbiota dependent condition

“…The biological function and molecular mechanisms of lncRNA in many kinds of human diseases in particular are constantly revealed [20,21]. Besides diseases, the role of lncRNA in development also has been reported [22]. LncRNAs have been reported that not expressed at each certain stages in development.…”

LncRNAs interacting with the translation machinery contribute to human neuronal differentiation

“…Long non-coding RNAs (lncRNAs) are >200nt and thought to lack the potential to encode proteins. LncRNAs are well known to play key roles in development and differentiation via several mechanisms (Dimartino et al, 2018;Tsagakis et al, 2020), such as the base-pairing of lnc-31 with Rock1 mRNA, to promote its translation during myoblast differentiation (Dimartino et al, 2018). ~40% of human lncRNAs are specifically expressed in the brain (Derrien et al, 2012), where they display precise spatiotemporal expression profiles (Ponting et al, 2009).…”