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Commentaries on Cutting Edge Science

Dawn of The Epi-LncRNAs

New Path from Myheart

Zhihua Wang, Yibin Wang
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https://doi.org/10.1161/CIRCRESAHA.114.305490
Circulation Research. 2015;116:235-236
Originally published January 15, 2015
Zhihua Wang
From the Molecular Biology Institute, Cardiovascular Research Laboratories, Departments of Anesthesiology, Physiology, and Medicine, David Geffen School of Medicine, University of California at Los Angeles.
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Yibin Wang
From the Molecular Biology Institute, Cardiovascular Research Laboratories, Departments of Anesthesiology, Physiology, and Medicine, David Geffen School of Medicine, University of California at Los Angeles.
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    • A long noncoding RNA protects the heart from pathological hypertrophy Han et al Nature. 2014;514:102–106.
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A long noncoding RNA protects the heart from pathological hypertrophy Han et al Nature. 2014;514:102–106.

Myheart is a cardiac-specific long-noncoding (lnc) RNA with targeted modulation of chromatin- modifying switching–defective/sucrose–nonfermenting complex via direct interaction with Brg1. Genetic induction of Myheart in mouse heart has a significant protective effect against the pathogenesis of heart failure. LncRNAs are emerging epigenetic regulators with potentially important roles in cardiac development and diseases.

Recent advances in genomics studies have revealed a profound new insight: the vast majority of our genome is no longer viewed as gene wasteland but actually littered with previously unrecognized harbors where many species of noncoding transcripts are produced.1 Among the different species of noncoding transcripts, lncRNAs, arbitrarily defined as transcripts longer than 200 nt with no or little translation propensity, represent a relatively new and understudied class. To date, majority of the nuclear lncRNAs are identified as histone modifiers that can epigenetically regulate transcriptome.1 These lncRNAs, which we refer here as Epi-lncRNAs, define a new paradigm of epigenetic regulation implicated in development and human diseases. In a recent report in Nature, Han et al identify the myosin heavy-chain–associated RNA transcripts (Myheart, or Mhrt) as an important regulator of cardiac hypertrophy and pathological remodeling through direct interaction with Brg1, the ATPase catalytic subunit of the switching defective/sucrose nonfermenting complex.2,3 This finding brings new spotlight to Epi-lncRNAs in cardiac gene regulation and pathogenesis and reveals Brg1 as a new lncRNA-regulated histone modifier (Figure).

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Figure.

Epigenetic regulations by long noncoding RNAs (lncRNAs). Regulatory circuit of α- and β-myosin heavy chain (Myh6 and Myh7) involving diverse epigenetic regulators.

The onset and progression of heart failure is associated with and driven by a concerted global change in cardiac gene expression, including re-expression of a subset of fetal genes.4,5 A well studied example is the dynamic switch between the α- and the β-myosin heavy chain isoforms during postnatal cardiac maturation and pathology. This switch is performed by coordinated and reciprocal up- and downregulation of Myh6 (gene for α-myosin heavy chain) and Myh7 (gene for β-myosin heavy chain), which are clustered in tandem on a highly conserved genomic locus. Previous work from Chang laboratory has demonstrated that epigenetic regulation through Brg1 is critical to both induction of Myh6 and repression of Myh7 involving direct interaction with histone deacytalase and poly (ADP-ribose) polymerase 1.6 Although chromatin remodeling has long been recognized as an important mechanism in cardiac transcriptome programming and reprogramming during development and pathogenesis, it remains a mystery as to how ubiquitously expressed chromatin remodeling complexes, such as switching defective/sucrose nonfermenting, can confer tissue-specific and coordinated regulation on their cardiac target genes. The discovery of Mhrt provides an intriguing mechanism for the underlying molecular process. Mouse Mhrt expression is induced during cardiomyocyte maturation and reduced in pressure overload–induced cardiac hypertrophy and heart failure, a profile perfectly correlated with the dynamic changes in the Myh7/Myh6 ratio during postnatal development and disease progression in heart. Transgenic mice expressing Mhrt show a blunted change in Myh7/Myh6 ratio in response to pressure overload. Mechanistically, by using procedures like RNA coimmunoprecipitation and EMSA (electrophoresis mobility shift assay), Han et al provide a series of evidence that Mhrt directly binds to the helicase domain of Brg1 which inhibits Brg1 chromatin-interacting capability, leading to selective repression of Myh6 and Mhrt expression in failing hearts. Thus, authors conclude that Mhrt regulates cardiac hypertrophic gene reprogramming via direct modulation of Brg1-mediated chromatin remodeling.

Mhrt transcripts are detected with a transcriptional start site overlapping but in the opposite direction with the Myh6 promoter, and the transcripts are extended into the Myh7 intron and exon sequences.3 Thus, Mhrt possesses both features of a promoter-associated lncRNA and an antisense lncRNA regarding Myh6 and Myh7, respectively. However, antisense effect unlikely plays a major role in Mhrt-mediated regulation considering the observations that Mhrt effect is dependent on Brg1 and that overexpressing Mhrt alone has no significant effect on Myh6/7 expression in cultured myocytes or transgenic hearts under basal condition. Furthermore, gene expression profiling and targeted chromatin-immunoprecipitation analysis have also revealed that the effect of Brg1/Mhrt interaction goes beyond cis-regulation at the Myh6/7 locus but affects in-trans other cardiac genes. Such broad effect explains why Mhrt expression in vivo can have such significant effect on the whole spectrum of pathological features in stressed heart. Indeed, Brg1 also acts on the Mhrt promoter itself forming a negative circuit regulation, implicating that the chromatin remodeling may be critical for establishing a stable expression level of target genes.

In addition to Mhrt, several other epigenetic mechanisms have been reported to control Myh7 and Myh6 expression during heart diseases. miR-208a and miR-208b, embedded in the introns of Myh6 and Myh7 genes, respectively, regulate Myh7 expression via downstream targets Thrap1 and Myostatin.7,8 A recent study identified another lncRNA cardiac hypertrophy–related factor that regulates Myh7 expression by acting as a sponge for miR-4892. The fact that different and diverse regulatory circuits converge at Myh6 and Myh7 gene cluster illustrate the importance of fine-tuning Myh7/Myh6 expression for normal cardiac function and the progression to disease under stress (Figure). In this regard, Myh6 and Myh7 are not simply sarcomere genes for the infrastructure of cardiac contraction,9 but also a central command for global cardiac gene regulation in development and diseases.

Despite these exciting new findings, for the vast majority of known cardiac lncRNAs, their biological functions remain elusive. Even in the case of Mhrt, the investigation opens many more questions than answers. Brg1 has been shown to interact with multiple transcription regulators in addition to histone deacytalase/poly (ADP-ribose) polymerase,10 and the effect of Mhrt interaction on their function remains to be studied. Finally, critical insights are still missing as to why the effect of Mhrt/Brg1 complex leads to opposite effects on Myh6 versus Myh7 expressions. Also demonstrated in both reports are the current challenges in lncRNA investigations. Simple sequence analysis is not sufficient to assure the noncoding feature of the putative lncRNAs, and rigorous experimental validation by ribosome profiling, in vitro translation, and targeted mutagenesis are required. In the absence of sequence constrains to lncRNA function, there is an urgent need to better understand the structural basis of lncRNA function. Poor sequence conservation also raised questions about clinical relevance and translation of lncRNA studies in animal models. Nevertheless, current progress has demonstrated great promise for lncRNAs as novel and potentially powerful biomarkers for disease diagnosis, prognosis, and stratification.11–13 The intricate regulatory circuits of lncRNA as demonstrated by cardiac hypertrophy–related factor and Mhrt provide potential new targets for therapeutic intervention. Considering the fact that vast majority of the genetic variants reside in the noncoding part of the human genome, better understanding lncRNA biology would offer new insights to the molecular basis of genetic diversity and personalized medicine for human diseases, including heart failure. Clearly, more investigations both at molecular level and systems level are required to advance our current knowledge to these new players in cardiac regulatory circuits.

Acknowledgments

This work is in part supported by grants HL103205, HL114437, HL122737.

Footnotes

  • The opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association.

  • Commentaries serve as a forum in which experts highlight and discuss articles (published here and elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine.

  • Commentaries are edited by Aruni Bhatnagar & Ali J. Marian.

  • © 2015 American Heart Association, Inc.

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Circulation Research
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    Zhihua Wang and Yibin Wang
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