Unlike protein-coded genes where the RNA transcript is an intermediate that is translated into a protein, non-coding RNAs (ncRNAs) function as an RNA. ncRNAs are divided into two classes based on length. Small non-coding RNAs include miRNAs, tRNAs and small nucleolar RNAs and the other class are long non-coding RNAs (lncRNAs). According to the 2019 version of the GENCODE project the human genome contains 19940 protein-coding genes, 16066 lncRNA genes and 7577 short ncRNA genes, of which 1881 are miRNAs. LncRNAs are defined as transcripts longer than 200 nt which have no protein coding potential. LncRNAs can be classified based on genomic localization and orientation, subcellular localization and mechanism of action.
lncRNAs have roles in diverse molecular mechanisms including epigenetic regulation, (post-)transcriptional gene regulation and compartmentalization. Most lncRNAs carry out their functions by binding to RNA-binging proteins such as transcription factors, chromatin modifiers and scaffolding proteins. Most lncRNAs bind to ribonucleoproteins (RNPs) and modulate their functions. Other LncRNAs bind to miRNAs and inhibit their interference on the expression of a third target. LncRNAs can also bind to DNA targets and attract chromatin modifier proteins, creating RNA-DNA-protein complexes in nuclear domains. LncRNAs can elicit a specific activity by controlling the localization, interaction and availability of effectors that regulate biological activity.
lncRNAs are classified into five groups based on their mechanism of action in a 2019 review in Journal of Molecular Cell Biology by Lozano-Vidal, Bink and Boon:
Signal: The expression of lncRNA is regulated in response to a stimulus, at a certain developmental time or in a specific cell type, which helps to integrate the response to the cellular context for quick regulatory changes.
Decoy: The lncRNA binds to an RNA-binding protein, RNA molecule, transcription factor or regulatory effector and inhibits its biological function by sequestering it. This group would include LncRNAs acting as miRNA sponges with the suggested term competitive endogenous RNAs (ceRNAs)
Guide: The lncRNA binds to a transcription factor or chromatin modifier and brings it to the target promoter to alter the expression of a certain gene. This mechanism can work on neighbouring genes (in cis) or on distant genes (in trans).
Scaffold: Distinct domains on the lncRNA bind several RNA-binding proteins and bring them together so they interact in macromolecular complexes.
Enhancer: The lncRNA interacts with both the promoter an enhancer of a gene and creates chromosomal looping which brings the regions together to stimulate gene expression
Cardiac aging and disease
lncRNAs are proposed as targets for interventional therapy in cardiovascular aging because of their emerging role in cardiac aging and disease. Developmental enhancer-associated lncRNAs have been shown to be reexpressed in stressed mouse and human hearts, which is potentially part of a reactivation of fetal gene program that occurs under pathological conditions.