Long noncoding RNAs in cardiovascular disease

Abstract

Purpose of review: Here, we review recent findings on the role of long noncoding RNAs (lncRNAs) in cardiovascular disease (CVD). In addition, we highlight some of the latest findings in lncRNA biology, providing an outlook for future avenues of lncRNA research in CVD.

Recent findings: Recent publications provide translational evidence from patient studies and animal models for the role of specific lncRNAs in CVD. The molecular effector mechanisms of these lncRNAs are diverse. Overall, cell-type selective modulation of gene expression is the largest common denominator. New methods, such as single-cell profiling and CRISPR/Cas9-screening, reveal additional novel mechanistic principles: For example, many lncRNAs establish RNA-based spatial compartments that concentrate effector proteins. Also, RNA modifications and splicing features can be determinants of lncRNA function.

Summary: lncRNA research is passing the stage of enumerating lncRNAs or recording simplified on-off expression switches. Mechanistic analyses are starting to reveal overarching principles of how lncRNAs can function. Exploring these principles with decisive genetic testing in vivo remains the ultimate test to discern how lncRNA loci, by RNA motifs or DNA elements, affect CVD pathophysiology.

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FIGURE 1

Classes and conceptual functions of lncRNAs. (a) Major classes of lncRNAs based on genomic orientation and relation to neighbouring genes. lincRNA (long intergenic noncoding RNA), as-lncRNA (antisense lncRNA), eRNA (enhancer RNA), PROMPT (promoter-upstream transcripts), uaRNA (noncoding RNA from 3’UTR of a protein-coding gene). (b--e) Major functions of lncRNAs. (b) Stable lincRNAs or more transient enhancer-like eRNAs as transcription and epigenetic regulators in cis and trans. Also, DNA elements or the processes of transcription and splicing can be functional determinants. (c) Role of low-abundance lncRNAs in seeding and maintaining different types of 3D-compartments. Shown is a nuclear condensate (nuclear body/ liquid-liquid phase separated structure) with IDRs/prion-like protein domains of an RBP and/or electrostatics (-/+) as building principles. (d) lncRNAs can affect protein activity. (e) A variety of other functions: lncRNAs may express peptides from previously undetected small ORFs, recruit effectors via RNA modifications, or bind other nucleic acids like RNAs (e.g. affecting stability, splicing or acting as competing endogenous RNA) or DNA (e.g. leading to R-loop formation and influencing transcription, replication, chromosome topology, damage repair). Ac, acetylation, example of activating histone tail posttranscriptional modification; IDR, intrinsically disordered domain; LLPS, liquid-liquid phase separated structure; P, phosphorylation as an example of protein activity change; TF, transcription factor.