Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction

Felician, Giulia; Collesi, Chiara; Lušić, Marina; Martinelli, Valentina; Ferro, Matteo Dal; Zentilin, Lorena; Zacchigna, Serena; Giacca, Mauro

doi:10.1161/circresaha.115.304517

Cited by 57 publications

(57 citation statements)

References 63 publications

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“…These studies have identified the acquisition of an epigenetic signature during cardiomyocyte maturation ( [60]. This indicates that adult cardiomyocytes may need to be epigenetically reset for efficient cell cycle re-induction before regeneration can occur (Fig.…”

Section: Dynamic Changes In the Epigenome During Cardiomyocyte Differmentioning

confidence: 99%

Resetting the epigenome for heart regeneration.

Quaife-Ryan

Sim

Porrello

et al. 2016

Seminars in Cell & Developmental Biology

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In contrast to adults, recent evidence suggests that neonatal mice are able to regenerate following cardiac injury. This regenerative capacity is reliant on robust induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. However, cardiac regenerative potential is lost as cardiomyocytes mature and permanently withdraw from the cell cycle shortly after birth. Recently, a handful of factors responsible for the regenerative disparity between the adult and neonatal heart have been identified, but the proliferative response of adult cardiomyoctes following modulation of these factors rarely reaches neonatal levels. The inefficient re-induction of proliferation in adult cardiomyocytes may be due to the epigenetic landscape, which drastically changes during cardiac development and maturation. In this review, we provide an overview of the role of epigenetic modifiers in developmental processes related to cardiac regeneration. We propose an epigentic framework for heart regeneration whereby adult cardiomyocyte identity requires resetting to a neonatal-like state to facilitate cell cycle re-entry and regeneration following cardiac injury.

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Section: Dynamic Changes In the Epigenome During Cardiomyocyte Differmentioning

confidence: 99%

Resetting the epigenome for heart regeneration.

Quaife-Ryan

Sim

Porrello

et al. 2016

Seminars in Cell & Developmental Biology

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“…While the study design does not permit exclusion of a possible contribution of systemic effects of 5azato the observed cardiac phenotype, the in vivo findings are consistent with two recent in vitro studies in cultured neonatal rat cardiomyocytes , which suggested that 5azainduces cardiomyocyte proliferation and inhibits endothelin-induced cardiomyocyte binucleation (Felician et al, 2014b;Kou et al, 2010;Paradis et al, 2014). These striking effects of 5azaon cardiomyocyte binucleation are particularly interesting given that hypomethylating agents such as 5azaare commonly used as anti-cancer drugs and have anti-proliferative effects in other cell types.…”

Section: Discussionsupporting

confidence: 81%

“…There is growing interest in the potential for induction of adult cardiomyocyte proliferation as a strategy for promoting cardiac regeneration following MI and a recent study suggests that epigenetics plays a key role in this process. Notch stimulation was shown to induce proliferation of neonatal cardiomyocytes, but not adult cardiomyocytes (Felician et al, 2014b). Felician et al demonstrated that the accumulation of repressive histone marks (H3K27me3) and DNA methylation marks at the promoters of Notch-responsive signalling effectors during neonatal development prevented Notch ligands from re-inducing proliferation in adult cardiomyocytes (Felician et al, 2014b).…”

Section: Global Epigenetic Modificationmentioning

confidence: 99%

“…Notch stimulation was shown to induce proliferation of neonatal cardiomyocytes, but not adult cardiomyocytes (Felician et al, 2014b). Felician et al demonstrated that the accumulation of repressive histone marks (H3K27me3) and DNA methylation marks at the promoters of Notch-responsive signalling effectors during neonatal development prevented Notch ligands from re-inducing proliferation in adult cardiomyocytes (Felician et al, 2014b). This indicates that adult cardiomyocytes may need to be epigenetically reset for efficient cell cycle re-induction before regeneration can occur (Figure 1.6).…”

Section: Global Epigenetic Modificationmentioning

confidence: 99%

“…A recent study has also identified numerous epigenetic modifications at Notch responsive promoters that appear to be important determinants of myocyte proliferative responses to Notch ligands (Felician et al, 2014a). Curiously, despite intensive interrogation of the roles of chromatin modifiers during cardiac development and disease, there have been few systematic studies on the impact of DNA methylation.…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

Sim

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Dynamic alterations of H3K4me3 and H3K27me3 at ADAM17 and Jagged‐1 gene promoters cause an inflammatory switch of endothelial cells

Katakia

Thakkar

Thakar

et al. 2021

Journal Cellular Physiology

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Histone protein modifications control the inflammatory state of many immune cells. However, how dynamic alteration in histone methylation causes endothelial inflammation and apoptosis is not clearly understood. To examine this, we explored two contrasting histone methylations; an activating histone H3 lysine 4 trimethylation (H3K4me3) and a repressive histone H3 lysine 27 trimethylation (H3K27me3) in endothelial cells (EC) undergoing inflammation. Through computer‐aided reconstruction and 3D printing of the human coronary artery, we developed a unique model where EC were exposed to a pattern of oscillatory/disturbed flow as similar to in vivo conditions. Upon induction of endothelial inflammation, we detected a significant rise in H3K4me3 caused by an increase in the expression of SET1/COMPASS family of H3K4 methyltransferases, including MLL1, MLL2, and SET1B. In contrast, EC undergoing inflammation exhibited truncated H3K27me3 level engendered by EZH2 cytosolic translocation through threonine 367 phosphorylation and an increase in the expression of histone demethylating enzyme JMJD3 and UTX. Additionally, many SET1/COMPASS family of proteins, including MLL1 (C), MLL2, and WDR5, were associated with either UTX or JMJD3 or both and such association was elevated in EC upon exposure to inflammatory stimuli. Dynamic enrichment of H3K4me3 and loss of H3K27me3 at Notch‐associated gene promoters caused ADAM17 and Jagged‐1 derepression and abrupt Notch activation. Conversely, either reducing H3K4me3 or increasing H3K27me3 in EC undergoing inflammation attenuated Notch activation, endothelial inflammation, and apoptosis. Together, these findings indicate that dynamic chromatin modifications may cause an inflammatory and apoptotic switch of EC and that epigenetic reprogramming can potentially improve outcomes in endothelial inflammation‐associated cardiovascular diseases.

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Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction

Cited by 57 publications

References 63 publications

Resetting the epigenome for heart regeneration.

Resetting the epigenome for heart regeneration.

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

Dynamic alterations of H3K4me3 and H3K27me3 at ADAM17 and Jagged‐1 gene promoters cause an inflammatory switch of endothelial cells

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