Long non-coding RNAs: novel regulators of cellular physiology and function

Abstract

Long non-coding RNAs were once considered as "junk" RNA produced by aberrant DNA transcription. They are now understood to play central roles in diverse cellular processes from proliferation and migration to differentiation, senescence and DNA damage control. LncRNAs are classed as transcripts longer than 200 nucleotides that do not encode a peptide. They are relevant to many physiological and pathophysiological processes through their control of fundamental molecular functions. This review summarises the recent progress in lncRNA research and highlights the far-reaching physiological relevance of lncRNAs. The main areas of lncRNA research encompassing their characterisation, classification and mechanisms of action will be discussed. In particular, the regulation of gene expression and chromatin landscape through lncRNA control of proteins, DNA and other RNAs will be introduced. This will be exemplified with a selected number of lncRNAs that have been described in numerous physiological contexts and that should be largely representative of the tens-of-thousands of mammalian lncRNAs. To some extent, these lncRNAs have inspired the current thinking on the central dogmas of epigenetics, RNA and DNA mechanisms.

Keywords: Long non-coding RNA; Pathophysiology; Physiology; ncRNA.

Figure 1

Publications about lncRNAs are existing in many different physiological areas. A–C Number of pubmed entries since 2008 for lncRNA and the individual tissue (A), cell type (B) or disease (C). PubMed searches were performed with the following terms: (“LncRNA” AND “search term”) OR (“Long non-coding RNA” AND “search term”) OR (“long non coding RNA” AND “search term”), as of date 5th October 2021.

Figure 2

Research outlines and lncRNA characteristics. A LncRNA transcripts are defined as non-coding RNAs longer than 200nt apparently lacking protein coding potential. Typically, the majority of lncRNAs are mRNA-like RNAs harbouring a 5′Cap and a polyA tail. B Genomic location of lncRNA genes. C LncRNAs can act in cis to regulate the immediate locus from which the lncRNA was transcribed, in trans to function elsewhere in the cell or trans-secreted. D For some lncRNA genes, functions on their gene itself, their transcript or peptide are known increasing the layer of complexity for their mode of operations.

Figure 3

lncRNAs in various physiological systems and processes. LncRNAs have been shown to be fundamental in almost all physiological systems and processes. Example lncRNAs are provided for the major physiological systems and for a select number of general physiological processes to highlight the ubiquitous nature of lncRNAs.

Figure 4

MAENLI, ANRIL, BACE1-AS1 and PCAT19 as examples of physiologically relevant lncRNA mechanisms. A For normal limb development, transcriptional activity of the MAENLI locus itself is required to activate EN1 expression. Homozygous loss or deletion of the MAENLI locus abolish its transcriptional activity leading to the loss of EN1 expression and limb malformation. B Linear ANRIL expression is increased in patients with coronary artery disease (CAD) patients and has pro-atherogenic functions through epigenetic rearrangements leading to altered expression of genes involved in atherosclerosis. Circular ANRIL, whose expression is decreased in CAD patients, is important for controlling rRNA maturation to protect from over-proliferation of vascular cells. C LncRNA BACE1-AS increases the mRNA stability of BACE1, resulting in an increased protein level of the β-secretase, which produces amyloid beta 1-42. This in turn activates BACE1-AS expression in a positive feedback loop. D PCAT19 has two isoforms, a long and a short isoform. The short form is dominating and promoted by binding of the transcription factors NKX3.1 and YY1 to the short isoform promoter. Two risk SNPs for prostate cancer are located within the promoter of PCAT19-short, preventing NKX3.1 and YY1 from binding. The SNP-affected PCAT19-short promoter switches to an enhancer, promoting the expression of PCAT19-long. PCAT19-long activates transcription of genes involved in cell cycle and the growth and metastasis of prostate cancer cells.