Editors' ChoiceCARDIOMYOPATHY

Superheroes and Villains of the Heart

See allHide authors and affiliations

Science Translational Medicine  15 Oct 2014:
Vol. 6, Issue 258, pp. 258ec175
DOI: 10.1126/scitranslmed.aaa0483

Superman usually chases the bad guys, right? Now try to imagine a world where their roles may be reversed and Superman sometimes ends up imprisoned. Clearly, this would be devastating news for the citizens of Metropolis. Han and colleagues recently discovered a cellular superhero—Myheart—whose Metropolis is the cardiomyocyte. Unfortunately for planet heart, Myheart is sometimes handcuffed by the “bad guys” it is policing; when running amok, they cause heart failure.

Han et al. showed that Myheart is a long noncoding RNA (lncRNA) that is only expressed in the heart of adult mice and humans. lncRNAs are RNA molecules of at least 100 nucleotides in length that do not encode proteins. Myheart’s nucleotide sequence is derived from the reverse complement of genomic segments located near or within the genes for myosin heavy chain 6 and 7 (Myh6 and Myh7). Interestingly, it is well established that a switch from transcription of Myh6 to Myh7 is seen in tissue protein expression patterns of failing hearts compared with normal controls.

One of Myheart’s main effects is down-regulation of BRG1, a chromatin-remodeling factor that is activated by pathological stress. The authors present evidence of a negative feedback loop: BRG1, the villain, is able to bind to the promoter of Myheart, thus repressing its transcription. BRG1, binding in this specific genomic segment, also down-regulates the transcription of a neighboring gene, Myh6, and promotes the pathological switch to Myh7. The researchers go on to show that Myheart repression by BRG1 plays a central role in heart failure pathogenesis. As a result, heart failure is prevented by knocking out Brg1 and can be rescued by overexpressing Myheart in mice. The final piece of the puzzle is the demonstration that low expression of MYHEART is commonly found in cardiac tissue of heart failure patients.

This study describes a lncRNA that is required to preserve normal organ function, defines a role for these molecules in chromatin biology, and offers potential therapeutic targets for heart failure patients. The next steps will be to determine how this peculiar reciprocal inhibitory circuit is regulated, what tips the balance in favor of BRG1 in some people but not others, and whether interfering with this system to favour MYHEART expression is safe.

P. Han et al., A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514, 102–106 (2014). [Abstract]

Navigate This Article