ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1

Han, Zhenbo; Wang, Xiuxiu; Xu, Zihang; Cao, Yang; Gong, Rui; Yu, Yang; Yu, Ying; Guo, Xiaofei; Liu, Shenzhen; Yu, Meixi; Ma, Wanbiao; Zhao, Yiming; Xu, Juan; Li, Xingda; Li, Shuainan; Xu, Yan; Song, Robert X.-D.; Xu, Binbin; Yang, Fan; Bamba, Djibril; Sukhareva, Natalia; Hong, Lei; Gao, Ming; Zhang, Wenwen; Zagidullin, Naufal; Zhang, Ying; Yang, Baofeng; Pan, Zhenwei; Cai, Benzhi

doi:10.7150/thno.47354

Cited by 116 publications

(103 citation statements)

References 34 publications

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“…Recent studies have unveiled a role in cardiomyocyte regeneration for ALKBH5 (α-ketoglutarate-dependent dioxygenase alkB homolog 5), a N 6 -methyladenosine eraser of messenger RNAs. Indeed, ALKBH5 expression levels decline in postnatal development and its overexpression promotes cardiomyocyte replication and cardiac regeneration following myocardial infarction in juvenile and adult mice, by increasing YAP translation (223). In contrast, knock out of methyltransferase-like 3 (METTL3), a N 6 -methyladenosine writer, whose expression levels raise postnatally, induces cardiomyocyte cell cycle re-entry, reduces scar size and boosts cardiac function after myocardial infarction, by regulating the miR-143-YAP axis (224).…”

Section: Epigenetic Regulationsmentioning

confidence: 99%

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Bongiovanni

Sacchi

Pra

et al. 2021

Front. Cardiovasc. Med.

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Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium.

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Section: Epigenetic Regulationsmentioning

confidence: 99%

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Bongiovanni

Sacchi

Pra

et al. 2021

Front. Cardiovasc. Med.

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“…Although the study of RNA modifications, epitranscriptomics remains in its infancy, methodological breakthroughs of the last decade have enabled identification of these modifications with such accuracy that their large-scale screening is rational [ 117 , 118 , 119 , 120 , 121 , 143 ]. Encouragingly, research findings suggest both m 6 A and A-to-I to act as contributors or even potential initiators and drivers for several cardiovascular physiological and pathological processes including cardiogenesis, angiogenesis, hypertension, hypertrophy, atherosclerosis, ischemia, ischemia-reperfusion, fibrosis, HF, congenital heart disease, stroke, aneurysms, as well as cardiac repair and regeneration [ 25 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 51 , 52 , 53 , 54 , 55 , 56 ]. Remarkably, the first indication for coronary atherosclerosis to be reflected in the m 6 A content of mRNAs and long non-coding RNAs of peripheral mononuclear cells with suggested involvement in its pathophysiology has just recently been reported [ 151 ].…”

Section: Discussionmentioning

confidence: 99%

“…Silencing or overexpression of enzymes controlling m 6 A abundance has revealed the role of m 6 A in driving immune reactivity, proliferation, apoptosis, and many intracellular processes including mRNA splicing, translation, and degradation [ 20 , 26 ], as well as miRNA biogenesis [ 27 ]. Moreover, reports from diverse fields of research [ 28 , 29 , 30 , 31 ], and in an array of cardiovascular pathologies [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ], provide evidence of m 6 A as a master post-transcriptional regulator.…”

Section: Introductionmentioning

confidence: 99%

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

Sikorski

Karjalainen

Blokhina

et al. 2021

IJMS

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Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.

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“…METTL14 induces endothelial cell inflammation and atherosclerotic plaque by enhancing the m6A modification of FOXO1 and promoting its expression. Meanwhile, the latest studies have shown that m6A can regulate cardiomyocyte renewal [ 31 ] and the “eraser” ALKBH5 can regulate the proliferation of cardiomyocytes by demethylating YTHDF1 [ 56 ]. The findings of these studies strongly indicate that m6A is important for heart development and can promote the proliferation and differentiation of stem cells in heart disease.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Patterns of N6‐Methyladenosine Profiles of Messenger RNA Correlated with the Cardiomyocyte Regenerability during the Early Heart Development in Mice

Yang

Shen

Cai

et al. 2021

Oxidative Medicine and Cellular Longevity

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N6-Methyladenosine (m6A) plays important roles in regulating mRNA processing. Despite rapid progress in this field, little is known about the role and mechanism of m6A modification in myocardial development and cardiomyocyte regeneration. Existing studies have shown that the heart tissues of newborn mice have the capability of proliferation and regeneration, but its mechanism, particularly its relation to m6A methylation, remains unknown. Methods. To systematically profile the mRNA m6A modification pattern in the heart tissues of mice at different developmental stages, we jointly performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) of heart tissues of mice, respectively, aged 1 day old, 7 days old, and 28 days old. Results. We identified the linkages and association between differentially expressed mRNA transcripts and hyper or hypomethylated m6A peaks in C57BL/6J mice at different heart developmental stages. Results showed that the amount of m6A peaks and the level of m6A modification were the lowest in the heart of mice at 1 day old. By contrast, heart tissues from 7-day-old mice tended to possess the most m6A peaks and the highest global m6A level. However, the m6A characteristics of myocardial tissue changed little after 7 days old as compared to that of 1 day old. Specifically, we found 1269 downmethylated genes of 1434 methylated genes in 7-day-old mouse heart tissues as compared to those in 1-day-old mice. Hypermethylation of some specific genes may correlate with the heart’s strong proliferative and regenerative capability at the first day after birth. In terms of m6A density, the tendency shifted from coding sequences (CDS) to 3 ′ -untranslated regions (3 ′ UTR) and stop codon with the progression of heart development. In addition, some genes demonstrated remarkable changes both in methylation and expression, like kiss1, plekha6, and megf6, which may play important roles in proliferation. Furthermore, signaling pathways highly related to proliferation such as “Wnt signaling pathway,” “ECM-receptor interaction,” and “cardiac chamber formation” were significantly enriched in 1-day-old methylated genes. Conclusions. Our results reveal a pattern that different m6A modifications are distributed in C57BL/6J heart tissue at different developmental stages, which provides new insights into a novel function of m6A methylation of mRNA in myocardial development and regeneration.

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ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1

Cited by 116 publications

References 34 publications

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

Dynamic Patterns of N6‐Methyladenosine Profiles of Messenger RNA Correlated with the Cardiomyocyte Regenerability during the Early Heart Development in Mice

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