Long Noncoding RNA Discovery in Cardiovascular Disease: Decoding Form to Function

Abstract

Despite significant improvements during the past 3 decades, cardiovascular disease remains a leading worldwide health epidemic. The recent identification of a fascinating group of mediators known as long noncoding RNAs (lncRNAs) has provided a wealth of new biology to explore for cardiovascular risk mitigation. lncRNAs are expressed in a highly context-specific fashion, and multiple lines of evidence implicated them in diverse biological processes. Indeed, abnormalities of lncRNAs have been directly linked with human ailments, including cardiovascular biology and disease. Of particular interest to the cardiovascular research community, dysregulation in lncRNA regulatory circuits have been associated with cardiac pathological hypertrophy, vascular disease, cell fate programming and development, atherosclerosis, dyslipidemia, and metabolic syndrome. Although techniques in interrogating noncoding RNAs are rapidly evolving, a major challenge in studying lncRNAs remains navigating through multiple technical constraints. In this review, we provide a road map for lncRNA discovery and interrogation in biological systems relevant to cardiovascular disease and highlight approaches to decipher their modes of action.

Keywords: RNA, untranslated; computational biology; genetics; heart diseases; risk factors.

Figure 1. Categories of RNA in mammalian cells

A, A schematic of major classes of RNA. Noncoding RNAs may resemble mRNA structurally, but some can have distinctive features, such as lack of polyA tail. B, Classification of noncoding RNAs >200 bp. qPCR indicates quantitative polymerase chain reaction.

Figure 2. Pipeline of long noncoding RNA (lncRNA) discovery and characterization

ASO indicates antisense oligonucleotide; ChiRP, chromatin isolation by RNA purification; qPCR, quantitative polymerase chain reaction; RAP, RNA antisense purification; and RIP, RNA immunoprecipitation.

Figure 3. Summary of techniques used to interrogate a long noncoding RNA’s (lncRNA) interactome

CHART indicates capture hybridization analysis of RNA targets; ChiRP, chromatin isolation by RNA purification; and RAP, RNA antisense purification.

Figure 4. Long noncoding RNA (lncRNA) loss and gain function strategies

ASO indicates antisense oligonucleotide; and TSS, transcription start site.