Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B

Vujić, Ana; Robinson, Emma; Ito, Mitsuteru; Haider, Syed; Ackers‐Johnson, Matthew; See, Kelvin; Methner, Carmen; Figg, N.; Brien, Patrick; Roderick, H. Llewelyn; Skepper, Jeremy N.; Ferguson‐Smith, Anne C.; Foo, Roger

doi:10.1016/j.yjmcc.2015.03.007

Cited by 50 publications

(38 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNMT3b KO mice die between E13.5 and 16.5 with abnormal heart structure (9). Tamoxifen‐induced cardiomyocyte‐specific loss of DNMT3b in adult heart for 3–4 wk results in compromised systolic function, increased interstitial fibrosis, and myosarcomeric disarray (10).…”

mentioning

confidence: 99%

Knockdown of DNA methyltransferase 3a alters gene expression and inhibits function of embryonic cardiomyocytes

et al. 2016

View full text Add to dashboard Cite

We previously found that in utero caffeine exposure causes down-regulation of DNA methyltransferases (DNMTs) in embryonic heart and results in impaired cardiac function in adulthood. To assess the role of DNMTs in these events, we investigated the effects of reduced DNMT expression on embryonic cardiomyocytes. siRNAs were used to knock down individual DNMT expression in primary cultures of mouse embryonic cardiomyocytes. Immunofluorescence staining was conducted to evaluate cell morphology. A video-based imaging assay and multielectrode array were used to assess cardiomyocyte contractility and electrophysiology, respectively. RNA-Seq and multiplex bisulfite sequencing were performed to examine gene expression and promoter methylation, respectively. At 72 h after transfection, reduced DNMT3a expression, but not DNMT1 or -3b, disrupted sarcomere assembly and decreased beating frequency, contractile movement, amplitude of field action potential, and cytosolic calcium signaling of cardiomyocytes. RNA-Seq analysis revealed that the DNMT3a-deficient cells had deactivated gene networks involved in calcium, endothelin-1, renin-angiotensin, and cardiac b-adrenergic receptor signaling, which were not inhibited by DNMT3b siRNA. Moreover, decreased methylation levels were found in the promoters of Myh7, Myh7b, Tnni3, and Tnnt2, consistent with the up-regulation of these genes by DNMT3a siRNA. These data show that DNMT3a plays an important role in regulating embryonic cardiomyocyte gene expression, morphology and function.-Fang, X., Poulsen, R. R., Wang-Hu, J., Shi, O., Calvo, N. S., Simmons, C. S., Rivkees, S. A., Wendler, C. C. Knockdown of DNA methyltransferase 3a alters gene expression and inhibits function of embryonic cardiomyocytes. FASEB J. 30, 3238-3255 (2016). www.fasebj.org

show abstract

mentioning

confidence: 99%

Knockdown of DNA methyltransferase 3a alters gene expression and inhibits function of embryonic cardiomyocytes

et al. 2016

View full text Add to dashboard Cite

show abstract

“…This study further demonstrated that DNMT3B deficiency alters methylation patterns and enhances splicing at a cryptic site of the sarcomeric gene, Myh7, and mediates the loss of exon 8. These results suggest that the loss of DNMT3B is associated with development and progression of reactive cardiac fibrogenesis through epigenetic modification of sarcomeric gene expression (Vujic et al, 2015). The contradictory results may arise simply due to the pharmacological inhibition of DNMT3B versus genetic deletion of DNMT3B where both have common as well as unique biological effects on the downstream events.…”

Section: Journal Of Cellular Physiologymentioning

confidence: 98%

Epigenetics in Reactive and Reparative Cardiac Fibrogenesis: The Promise of Epigenetic Therapy

Ghosh

Rai

Flevaris

et al. 2017

Journal Cellular Physiology

View full text Add to dashboard Cite

Epigenetic changes play a pivotal role in the development of a wide spectrum of human diseases including cardiovascular diseases, cancer, diabetes, and intellectual disabilities. Cardiac fibrogenesis is a common pathophysiological process seen during chronic and stress-induced accelerated cardiac aging. While adequate production of extracellular matrix (ECM) proteins is necessary for post-injury wound healing, excessive synthesis and accumulation of extracellular matrix protein in the stressed or injured hearts causes decreased or loss of lusitropy that leads to cardiac failure. This self-perpetuating deposition of collagen and other matrix proteins eventually alter cellular homeostasis; impair tissue elasticity and leads to multi-organ failure, as seen during pathogenesis of cardiovascular diseases, chronic kidney diseases, cirrhosis, idiopathic pulmonary fibrosis, and scleroderma. In the last 25 years, multiple studies have investigated the molecular basis of organ fibrosis and highlighted its multi-factorial genetic, epigenetic, and environmental regulation. In this minireview, we focus on five major epigenetic regulators and discuss their central role in cardiac fibrogenesis. Additionally, we compare and contrast the epigenetic regulation of hypertension-induced reactive fibrogenesis and myocardial infarction-induced reparative or replacement cardiac fibrogenesis. As microRNAs-one of the major epigenetic regulators-circulate in plasma, we also advocate their potential diagnostic role in cardiac fibrosis. Lastly, we discuss the evolution of novel epigenetic-regulating drugs and predict their clinical role in the suppression of pathological cardiac remodeling, cardiac aging, and heart failure. J. Cell. Physiol. 232: 1941-1956, 2017. © 2016 Wiley Periodicals, Inc.

show abstract

“…RASSF1A is a regulatory tumor suppressor, involved in fibroblast activation and cardiac fibrosis pathogenesis (42). Cardiac specific deletion of DNMT3B in adult mouse hearts leads to an accelerated progression to severe systolic insufficiency and promotes widespread myocardial interstitial fibrosis (43). Long-term local tissue hypoxia can lead to disrupted ventricular remodeling and cardiac fibrosis (44).…”

Section: Dna Methylationmentioning

confidence: 99%

DNA methylation regulated gene expression in organ fibrosis

Zhang

Lyu

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

DNA methylation is a major epigenetic mechanism to regulate gene expression. Epigenetic regulation, including DNA methylation, histone modifications and RNA interference, results in heritable changes in gene expression independent of alterations in DNA sequence. Epigenetic regulation often occurs in response to aging and environment stimuli, including exposures and diet. Studies have shown that DNA methylation is critical in the pathogenesis of fibrosis involving multiple organs sytems, contributing to significant morbidity and mortality. Aberrant DNA methylation can silence or activate gene expression patterns that drive the fibrosis process. Fibrosis is a pathological wound healing process in response to chronic injury. It is characterized by excessive extracellular matrix production and accumulation, which eventually affects organ architecture and results in organ failure. Fibrosis can affect a wide range of organs, including the heart and lungs, and have limited therapeutic options. DNA methylation, like other epigenetic process, is reversible, therefore regarded as attractive therapeutic interventions. Although epigenetic mechanisms are highly interactive and often reinforcing, this review discusses DNA methylation-dependent mechanisms in the pathogenesis of organ fibrosis, with focus on cardiac and pulmonary fibrosis. We discuss specific pro- and anti-fibrotic genes and pathways regulated by DNA methylation in organ fibrosis; we further highlight the potential benefits and side-effects of epigenetic therapies in fibrotic disorders.

show abstract

Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B

Cited by 50 publications

References 28 publications

Knockdown of DNA methyltransferase 3a alters gene expression and inhibits function of embryonic cardiomyocytes

Knockdown of DNA methyltransferase 3a alters gene expression and inhibits function of embryonic cardiomyocytes

Epigenetics in Reactive and Reparative Cardiac Fibrogenesis: The Promise of Epigenetic Therapy

DNA methylation regulated gene expression in organ fibrosis

Contact Info

Product

Resources

About