Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo

Gilsbach, Ralf; Schwaderer, Martin; Preißl, Sebastian; Grüning, Björn; Kranzhöfer, David K.; Schneider, Pedro; Nührenberg, Thomas; Mulero‐Navarro, Sonia; Weichenhan, Dieter; Braun, Christian; Dreßen, Martina; Jacobs, Adam; Lahm, Harald; Doenst, Torsten; Backofen, Rolf; Krane, Markus; Gelb, Bruce D.; Hein, Lutz

doi:10.1038/s41467-017-02762-z

Cited by 190 publications

(176 citation statements)

References 73 publications

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“…There is increasing evidence that aberrant gene expression, orchestrated by transcription factors and epigenetic processes such as non‐coding RNAs, DNA and histone modifications, represents a key event in heart failure and could thus offer new ways for therapeutic intervention . While methylation of DNA seems to be important during maturation of the heart, the role of RNA modifications has not been studied in detail until now.…”

Section: Introductionmentioning

confidence: 99%

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Berulava

Buchholz

Vakhtang

et al. 2019

European J of Heart Fail

216

235

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Aims Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development. Methods and results We analysed m6A RNA methylation via next‐generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription‐independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice. Conclusions We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription‐independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions.

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Section: Introductionmentioning

confidence: 99%

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Berulava

Buchholz

Vakhtang

et al. 2019

European J of Heart Fail

216

235

View full text Add to dashboard Cite

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“…J Physiol 598.14 transcriptomic analysis has been used to: elucidate stage-specific regulatory networks guiding cardiac development and maturation ; identify nucleosome and histone-modifying genes in maturation (van den Berg et al 2015); identify the role of Let-7 family of microRNAs in guiding CM maturation through metabolic switch (Kuppusamy et al 2015); and identify miR-200c as a regulator of mature ion channel expression and calcium handling (Poon et al 2018). In concert with chromatin immunoprecipitation-sequencing (ChIP-seq), transcriptomic analyses have also been used to develop a stronger understanding of epigenetic dynamics of maturation (Sim et al 2015;Gilsbach et al 2018). Lastly, transcriptomics has provided a powerful tool to benchmark the maturation status of in vitro-generated CM tissues (Kuppusamy et al 2015;van den Berg et al 2015;DeLaughter et al 2016).…”

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confidence: 99%

Regulation of cardiomyocyte maturation during critical perinatal window

Kannan

Kwon

2019

The Journal of Physiology

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A primary limitation in the use of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) for both patient health and scientific investigation is the failure of these cells to achieve full functional maturity. In vivo, cardiomyocytes undergo numerous adaptive structural, functional and metabolic changes during maturation. By contrast, PSC-CMs fail to fully undergo these developmental processes, instead remaining arrested at an embryonic stage of maturation. There is thus a significant need to understand the biological processes underlying proper CM maturation in vivo. Here, we discuss what is known regarding the initiation and coordination of CM maturation. We postulate that there is a critical perinatal window, ranging from embryonic day 18.5 to postnatal day 14 in mice, in which the maturation process is exquisitely sensitive to perturbation. While the initiation mechanisms of this process are unknown, it is increasingly clear that maturation proceeds through interconnected regulatory circuits that feed into one another to coordinate concomitant structural, functional and metabolic CM maturation. We highlight PGC1α, SRF and the MEF2 family as transcription factors that may potentially mediate this cross-talk. We lastly discuss several emerging technologies that will facilitate future studies into the mechanisms of CM maturation. Further study will not only produce a better understanding of its key processes, but provide practical insights into developing a robust strategy to produce mature PSC-CMs. Abstract figure legendHere, we postulate that there is a critical window, ranging from embryonic day 18.5 to postnatal day 14 in mice, in which interconnected regulatory circuits enable coordinated, concomitant structural, functional and metabolic cardiomyocyte maturation.

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“…DNA methylation and histone modifications are the most common mechanisms of epigenetic modulation of gene expression. It has been suggested that histone modification may contribute to the reprogramming of cardiac gene expression in heart failure, but the role of DNA methylation is far less well defined. Several studies have investigated genome‐wide DNA methylation in failing hearts.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent studies also using human cardiac tissue revealed differences in methylation of genes involved in pathways related to heart disease, which may provide an opportunity for differential diagnosis of heart failure . Gilsbach et al provided information on how DNA methylation patterns change during developmental and pathological remodelling; interestingly, in a pressure overload model of heart failure, the DNMT3A‐catalyzed patterns of DNA methylation detected in isolated cardiomyocytes were similar to those seen during development.…”

Section: Introductionmentioning

confidence: 97%

In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

et al. 2020

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Aims Although distinct DNA methylation patterns have been reported, its localization and roles remain to be defined in heart failure. We investigated the cellular and subcellular localization of DNA methylation and its pathophysiological significance in human failing hearts. Methods and results Using left ventricular (LV) endomyocardial biopsy specimens from 75 patients with dilated cardiomyopathy (DCM; age: 58 ± 14 years old, %female: 32%) and 20 patients without heart failure (controls; age: 56 ± 17 years old, %female: 45%), we performed immunohistochemistry and immunoelectron microscopy for methylated DNA, 5methylcytosine (5-mC). We next investigated possible relations of the incidence of 5-mC-positive (%5-mC + ) cardiomyocytes with clinicopathological parameters. Immunopositivity for 5-mC was detected in the cardiomyocytes and other cell types. The %5-mC + cardiomyocytes was significantly greater in DCM hearts than in controls (57 ± 13% in DCM vs. 25 ± 12% in controls, P < 0.0001). The localization of 5-mC immunopositivity in cardiomyocyte nuclei coincided well with that of heterochromatin, as confirmed by immunoelectron microscopy. Substantial DNA methylation was also observed in interstitial noncardiomyocytes, but the incidences did not differ between control and DCM hearts (39 ± 7.9% in DCM vs. 41 ± 10% in controls, P = 0.4099). In DCM patients, the %5-mC + cardiomyocytes showed a significant inverse correlation with LV functional parameters such as heart rate (r = 0.2391, P = 0.0388), end-diastolic pressure (r = 0.2397, P = 0.0397), and ejection fraction (r = À0.2917, P = 0.0111) and a positive correlation with LV dilatation (volume index at diastole; r = 0.2442, P = 0.0347; and volume index at systole; r = 0.3136, P = 0.0062) and LV hypertrophy (mass index; r = 0.2287, P = 0.0484)-that is, LV remodelling parameters. No significant correlations between DNA methylation and the histological parameters of the biopsies, including cardiomyocyte hypertrophy, fibrosis, and inflammatory cell infiltration, were noted. Conclusions The present study revealed increased nuclear DNA methylation in cardiomyocytes, but not other cell types, from DCM hearts, with predominant localization in the heterochromatin. Its significant relations with LV functional and remodelling parameters imply a pathophysiological significance of DNA methylation in heart failure.

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Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo

Cited by 190 publications

References 73 publications

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Changes in m6A RNA methylation contribute to heart failure progression by modulating translation

Regulation of cardiomyocyte maturation during critical perinatal window

In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

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