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Rio P Juni, Reinier A Boon, CARMA: what goes around, comes around for the heart, Cardiovascular Research, Volume 118, Issue 10, June 2022, Pages 2227–2228, https://doi.org/10.1093/cvr/cvac041
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This editorial refers to ‘The conserved long non-coding RNA CARMA regulates cardiomyocyte differentiation’ by M. Kay et al., https://doi.org/10.1093/cvr/cvab281.
Unlike skeletal muscles, cardiac muscle does not efficiently regenerate. All adult striated muscle cells are incapable of sufficient proliferation to allow repair. However, skeletal muscle fibres can regenerate through activation of satellite cells and subsequent fusion with pre-existing muscle fibres. There is no such trick in the heart. This is one of the main reasons why patients with heart disease, even after survival of the primary ischaemic event such as an acute myocardial infarction, suffer from heart failure. The damaged myocardium can simply not be repaired. The holy grail is to find ways to induce cardiac repair, either by stem cell-mediated generation of new cardiomyocytes or by stimulating pre-existing cardiomyocytes to undergo proliferation. Both processes take place during embryonic development of the heart, and it is in this process that we can learn how to stimulate differentiation into and proliferation of cardiomyocytes.1
We know quite a lot already about transcription factors and signalling cascades that contribute to cardiac development, but the role of non-coding RNAs is still largely undiscovered. Non-coding RNAs, which are transcribed from the regions of the genome that do not encode proteins, have gained considerable interest in the last decades, as many of these molecules have been identified to play key regulatory roles in cells of the cardiovascular (and other) systems.2 In this issue of Cardiovascular Research, the team led by Pedrazzini reports the discovery of the lncRNA they call CARdiomyocyte Maturation-Associated lncRNA (CARMA).3 CARMA is enriched in cardiomyocytes and is characterized by enhanced expression in cardiac differentiation from human embryonic stem cells.
The genomic localization of CARMA is interesting, because it lies next to a well-known muscle-enriched microRNA (miRNA) cluster (miR-1 and miR-133), which also increases in expression upon cardiac differentiation.4 The expression patterns of CARMA, miR-1, and miR-133 show a striking overlap and are likely due to these transcripts sharing a promoter region. Interestingly, CARMA seems to act as a transcriptional repressor of the miR-1/miR-133 cluster, acting as a negative feedback loop to control expression of these developmentally important miRNAs. How this works exactly is not studied further, but the authors do show that miR-133 is able to bind and repress CARMA. This may function as a positive feedforward loop controlling a miR-133/CARMA switch, in which CARMA induction represses miR-133, thereby releasing the inhibition of CARMA expression. That miRNAs bind to lncRNAs is not something new, on the contrary, it seems a vastly overrepresented mechanism in the literature, where lncRNAs are frequently proposed to ‘sponge’ miRNAs, thereby inhibiting the miRNA and allowing for target de-repression. Even though this mechanism is not excluded for CARMA, the cis-regulatory inhibition of transcription of the primary miRNA transcript seems much more likely. The notion that regulation of the miRNA then only serves as a feedforward loop for CARMA expression is very interesting and suggests that instead of functioning as a miRNA ‘sponge’, in many instances it is just the case that the miRNA is regulating the expression of the lncRNA and not vice versa.
The main mode of action for CARMA is regulating miR-133a (and miR-1) expression and function (Figure 1). One of the targets of miR-133a is the transcription factor Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJ), an integral part of the Notch signalling cascade. RBPJ, in turn, represses the expression of yet another set of lncRNAs. In the end, these two lncRNAs (linc1230 and linc1335) determine cardiac mesoderm phenotype. This cascade explains how an increase in CARMA results in a repression of miR-133 that induces RBPJ to inhibit linc1230 and linc1335 and neuroectoderm specification, which enhances cardiac differentiation. In the end, this paper describes the identification of three lncRNAs, CARMA, linc1230, and linc1335, which all regulate the fine balance between neuroectodermal and cardiac mesodermal specification. The mechanism by which CARMA regulates this balance (via miR-133a-mediated regulation of Notch signalling) is convincingly shown by Kay et al.,3 but how linc1230 and linc1335 repress neuroectodermal differentiation remains to be shown. It is also not clear whether linc1230 and linc1335 are required for full repression of neuroectodermal differentiation by CARMA downstream signalling. On the other side, it is also not known how CARMA expression is regulated during development, and even though the authors propose this regulation involves polycomb proteins and E2F6, there is no experimental proof that shows that this is indeed the case.
Finally, this study shows a potential clinical therapeutic target that may be used to stimulate regeneration of the myocardium. However, timing and (cell-specific) delivery of compounds or gene therapeutics that would be able to utilize the CARMA axis is an issue that makes enhancement of cardiac developmental programmes in order to stimulate regeneration problematic.5 Together, the findings reported by Kay et al.3 reveal a novel axis regulating cardiac development and providing yet another potentially therapeutic non-coding RNA target in cardiac regeneration.
Conflicts of interest: R.A.B. has several issued patents on ncRNAs and R.P.J. has nothing to declare.
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Author notes
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.