Emerging Roles for DNA 6mA and RNA m6A Methylation in Mammalian Genome

Xie, Leijie; Zhang, Xiaosong; Xie, Jiaxiang; Xu, Yanru; Li, Xiao-Jiang; Lin, Li

doi:10.3390/ijms241813897

Cited by 5 publications

(1 citation statement)

References 217 publications

(261 reference statements)

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“…These compounds, 1-methyladenine (1 mA) and 3-methyladenine (3 mA), are considered by many to be the result of alkylation damage in DNA and, thus, are significant in the study of genome stability and DNA repair [20]. Recent developments in detection methods have shown DNA N6-methyl deoxyadenosine (6 mA) as a methylation alteration at the sixth position of adenine in DNA, with an impact on neurodegeneration [21].…”

Section: • Dna Methylationmentioning

confidence: 99%

An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions

Lossi,

Castagna,

Merighi

2024

IJMS

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Epigenetic changes are changes in gene expression that do not involve alterations to the DNA sequence. These changes lead to establishing a so-called epigenetic code that dictates which and when genes are activated, thus orchestrating gene regulation and playing a central role in development, health, and disease. The brain, being mostly formed by cells that do not undergo a renewal process throughout life, is highly prone to the risk of alterations leading to neuronal death and neurodegenerative disorders, mainly at a late age. Here, we review the main epigenetic modifications that have been described in the brain, with particular attention on those related to the onset of developmental anomalies or neurodegenerative conditions and/or occurring in old age. DNA methylation and several types of histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation) are major players in these processes. They are directly or indirectly involved in the onset of neurodegeneration in Alzheimer’s or Parkinson’s disease. Therefore, this review briefly describes the roles of these epigenetic changes in the mechanisms of brain development, maturation, and aging and some of the most important factors dynamically regulating or contributing to these changes, such as oxidative stress, inflammation, and mitochondrial dysfunction.

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Section: • Dna Methylationmentioning

confidence: 99%

An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions

Lossi,

Castagna,

Merighi

2024

IJMS

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METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs

Jin,

Han,

Wang

et al. 2024

Int J Oral Sci

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Bisphosphonate-related osteonecrosis of jaw (BRONJ) is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells (BMSCs). Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders. However, the role of corin in BRONJ-related BMSCs dysfunction remains unclarified. A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation. Corin knockdown inhibits BMSCs osteogenic differentiation, whereas corin overexpression or soluble corin (sCorin) exerts a promotion effect. Furthermore, corin expression is negatively regulated by bisphosphonates (BPs). Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability. Mechanistically, we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation. PD98059 (a selective ERK inhibitor) blocks the corin-mediated promotion effect. With regard to the high methylation level of corin during osteogenic differentiation, we apply a non-selective m6A methylase inhibitor, Cycloleucine, which also blocks the corin-mediated promotion effect. Furthermore, we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function, indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability. To conclude, our study reveals that corin reverses BPs-induced BMSCs dysfunction, and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway. We hope this brings new insights into future clinical treatments for BRONJ.

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Epigenetics-targeted drugs: current paradigms and future challenges

Dai,

Qiao,

Fang

et al. 2024

Sig Transduct Target Ther

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Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA regulation. These mechanisms and their associated enzymes convey genetic information independently of DNA base sequences, playing essential roles in organismal development and homeostasis. Conversely, disruptions in epigenetic landscapes critically influence the pathogenesis of various human diseases. This understanding has laid a robust theoretical groundwork for developing drugs that target epigenetics-modifying enzymes in pathological conditions. Over the past two decades, a growing array of small molecule drugs targeting epigenetic enzymes such as DNA methyltransferase, histone deacetylase, isocitrate dehydrogenase, and enhancer of zeste homolog 2, have been thoroughly investigated and implemented as therapeutic options, particularly in oncology. Additionally, numerous epigenetics-targeted drugs are undergoing clinical trials, offering promising prospects for clinical benefits. This review delineates the roles of epigenetics in physiological and pathological contexts and underscores pioneering studies on the discovery and clinical implementation of epigenetics-targeted drugs. These include inhibitors, agonists, degraders, and multitarget agents, aiming to identify practical challenges and promising avenues for future research. Ultimately, this review aims to deepen the understanding of epigenetics-oriented therapeutic strategies and their further application in clinical settings.

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Emerging Roles for DNA 6mA and RNA m6A Methylation in Mammalian Genome

Cited by 5 publications

References 217 publications

An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions

An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions

METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs

Epigenetics-targeted drugs: current paradigms and future challenges

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