Linc-ing the Noncoding Genome to Heart Function

Cardiovascular disease is a major health concern worldwide. Hypertensive stress, inflammation or injury of heart muscle, and abnormal rhythms due to valve dysfunction can contribute to the enlargement of cardiac cells known as ‘pathological’ hypertrophy. Pathological hypertrophy can further lead to fibrosis or scarring of tissue, reduced capillary densities, increased levels of proinflammatory cytokines, dysregulation of signaling pathways, autophagy, and abnormal cardiomyocyte/non-cardiomyocyte interactions.

The remarkable potential of noncoding RNAs (ncRNAs) to orchestrate various developmental events and disease progression is being increasingly recognized and ncRNAs have emerged as master regulators of gene expression. Thus, the enormous repertoire of ncRNAs may harbor promising avenues for the development of therapeutic strategies to treat various cardiomyopathies.

lncRNAs comprise the most dynamic class of ncRNAs and are defined as transcripts longer than 200 nucleotides. They can be further categorized as intergenic (e.g., H19), intronic, exonic, sense, or antisense [e.g., HOX transcript antisense RNA (Hotair)] depending on their genomic location relative to protein-coding genes. lncRNAs undergo transcription mediated by RNA polymerase II or III, splicing, 5′ capping, and polyadenylation. The ability of lncRNAs to interact with many genes in trans (distantly located genes) or cis (neighboring genes) allows them to influence several genes and proteins.

Long Noncoding RNAs (lncRNAs) in Cardiac Hypertrophy

Several conserved lncRNAs have been identified as critical regulators of pathological hypertrophy in mice and humans. For instance, the lncRNA myosin heavy chain-associated RNA transcript (Mhrt) sequesters the Brg1–Hdac–Parp complex and inhibits chromatin targeting of Brg1 to hypertrophic genes in healthy murine hearts. The stress signal induces a hypertrophic response when high levels of Brg1 repress Mhrt expression and simultaneously activates transcription from hypertrophic genes. Antisense oligonucleotides (ASOs) can be administered to inhibit endogenous noncoding RNAs or modified RNA (modRNA) molecules might be designed for (re)activation of the lncRNA. Delivery might be achieved via viral particles, nanoparticles, or injection of free molecules. Chast, cardiac hypertrophy-associated transcript; Chaer, cardiac hypertrophy-associated epigenetic regulator; Chrf, cardiac hypertrophy related factor.

Chatterjee S, Bär C, Thum T. (2017) Linc-ing the Noncoding Genome to Heart Function: Beating Hypertrophy. Trends Mol Med [Epub ahead of print]. [abstract]

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