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Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms. [Display omitted] • GSCs exhibit high activity of the malate-aspartate shuttle (MAS) • Targeting malate dehydrogenase 2 (MDH2) reduces GSC proliferation and stemness • MDH2 regulates m6A modifications of PDGFRB mRNA via αKG-dependent ALKBH5 inhibition • MDH2 inhibition augments the efficacy of dasatinib against GSCs Lv et al. find that stem-like tumor cells preferentially activate the malate-aspartate shuttle (MAS), which represses levels of α-ketoglutarate, a metabolite co-factor for the mRNA demethylase ALKBH5, to reprogram the epitranscriptome and maintain tumor stemness. Targeting this tumor-associated metabolic pathway through malate dehydrogenase 2 sensitizes highly resistant cancer cells to targeted therapeutics. Collectively, tumors reprogram their metabolic states to promote RNA diversity and maintenance of cancer stem cells, providing therapeutic vulnerabilities. [ABSTRACT FROM AUTHOR]

RNA modifications affect key stages of the RNA life cycle, including splicing, export, decay, and translation. Epitranscriptomic regulations therefore significantly influence cellular physiology and pathophysiology. Here, we selected some of the most abundant modifications and reviewed their roles in the heart and in cardiovascular diseases: N6-methyladenosine (m6A), N6,2‘-O-dimethyladenosine (m6Am), N¹-methyladenosine (m¹A), pseudouridine (Ψ), 5-methylcytidine (m5C), and inosine (I). Dysregulation of epitranscriptomic machinery affecting these modifications vastly changes the cardiac phenotype and is linked with many cardiovascular diseases such as myocardial infarction, cardiomyopathies, or heart failure. Thus, a deeper understanding of these epitranscriptomic changes and their regulatory mechanisms can enhance our knowledge of the molecular underpinnings of prevalent cardiac diseases, potentially paving the way for novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is an abundant mRNA modification affecting mRNA stability and protein expression. It is a highly dynamic process, and its outcomes during postnatal heart development are poorly understood. Here we studied m6A machinery in the left ventricular myocardium of Fisher344 male and female rats (postnatal days one to ninety; P1-P90) using Western Blot. A downward pattern of target protein levels (demethylases FTO and ALKBH5, methyltransferase METTL3, reader YTHDF2) was revealed in male and female rats during postnatal development. On P1, the FTO protein level was significantly higher in males compared to females. [ABSTRACT FROM AUTHOR]

Aging is characterized by a gradual and progressive decline in system integrity that occurs with advancing chronological age. Although it is a physiological process, aging is associated with a myriad of age-related diseases (ARDs), including frailty, sarcopenia, chronic obstructive pulmonary disease, cardiovascular disease, cancer, and neurodegenerative diseases. While not exclusively ARDs, many of these diseases lead to death, a lesser quality of life, and increased healthcare costs for individuals and systems. ARDs share several underlying molecular mechanisms, such as cellular damage, inflammation, DNA methylation changes, stem cells exhaustion, and DNA mutations, which have been outlined as hallmarks of aging. Evidence suggests that environmental exposures, including but not limited to metals, air pollution, endocrine-disrupting chemicals, and noise, may accelerate biological aging. Over the past few years, aging research has identified new molecular biomarkers of the aging process. When applied to investigate environmental influences, these biomarkers can help identify individuals who are particularly susceptible to the influences of environmental exposures on aging processes and therefore guide in implementing possible preventive measures. [ABSTRACT FROM AUTHOR]

Like DNA and proteins, RNA is subject to numerous (over 160) covalent modifications which play critical roles to regulate RNA metabolism. Among these modifications, N6-methyladenosine (m6A) is the most prevalent RNA methylation on mRNA which occurs on around 25% of transcripts. The recent studies demonstrated that m6A participates in many aspects of RNA processing, including splicing, nuclear exporting, translation, stabilization, etc. Therefore, it revealed a new layer of regulatory mechanism for gene expression and has been termed "RNA Epigenetics" or "Epitranscriptomics". RNA m6A is regulated and exerts its functions by three groups of "m6A RNA modifiers" including m6A methyltransferases (writers), m6A demethylases (erasers), and m6A binding proteins (readers). In this review, we would summarize and discuss the current understandings of the roles of the conventional m6A RNA modifiers in human cancers. [ABSTRACT FROM AUTHOR]

Pancreatic β-cells adapt to high metabolic demand by expanding their β-cell mass and/or enhancing insulin secretion to maintain glucose homeostasis. Type 2 diabetes (T2D) is typically characterized by β-cell decompensation. The current review focuses on summarizing the "omics" and "epi-omics" approaches that particularly focus on addressing the β-cell adaptation to insulin resistance and T2D. The molecular mechanisms underlying successful versus compromised β-cell adaptation to insulin resistance are not entirely understood. The last decade has seen an exponential increase in the use of "omics" and "epi-omics" approaches to dissect pathophysiology of metabolic diseases. One recent example is the emergence of m6A mRNA methylation as a new layer of regulation of gene expression with the potential to impact diverse physiological processes in metabolic cells. [ABSTRACT FROM AUTHOR]

Viral epitranscriptomics is a newly emerging field that has identified unique roles for RNA modifications in modulating life cycles of RNA viruses. Despite the observation of a handful of modified viral RNAs five decades ago, very little was known about how these modifications regulate viral life cycles, until recently. Here we review the pro- and anti-viral effects of methyl-6-adenosine in distinct viral life cycles, the role of 2′ O-methyl modifications in RNA stability and innate immune sensing, and functions of adenosine to inosine modifications in retroviral life cycles. With roles for over 100 modifications in RNA still unknown, this is a rapidly emerging field that is destined to suggest novel antiviral therapies. [ABSTRACT FROM AUTHOR]

RNA plays central roles in biology and novel functions and regulation mechanisms are constantly emerging. To accomplish some of their functions within the cell, RNA molecules undergo hundreds of chemical modifications from which N6-methyladenosine (m 6 A), inosine (I), pseudouridine (ψ) and 5-methylcytosine (5mC) have been described in eukaryotic mRNA. Interestingly, the m 6 A modification was shown to be reversible, adding novel layers of regulation of gene expression through what is now recognized as epitranscriptomics. The development of molecular mapping strategies coupled to next generation sequencing allowed the identification of thousand of modified transcripts in different tissues and under different physiological conditions such as viral infections. As intracellular parasites, viruses are confronted to cellular RNA modifying enzymes and, as a consequence, viral RNA can be chemically modified at some stages of the replication cycle. This review focuses on the chemical modifications of viral RNA and the impact that these modifications have on viral gene expression and the output of infection. A special emphasis is given to m 6 A, which was recently shown to play important yet controversial roles in different steps of the HIV-1, HCV and ZIKV replication cycles. [ABSTRACT FROM AUTHOR]

Summary Many viral RNAs are modified by methylation of the N 6 position of adenosine (m 6 A). m 6 A is thought to regulate RNA splicing, stability, translation, and secondary structure. Influenza A virus (IAV) expresses m 6 A-modified RNAs, but the effects of m 6 A on this segmented RNA virus remain unclear. We demonstrate that global inhibition of m 6 A addition inhibits IAV gene expression and replication. In contrast, overexpression of the cellular m 6 A “reader” protein YTHDF2 increases IAV gene expression and replication. To address whether m 6 A residues modulate IAV RNA function in cis , we mapped m 6 A residues on the IAV plus (mRNA) and minus (vRNA) strands and used synonymous mutations to ablate m 6 A on both strands of the hemagglutinin (HA) segment. These mutations inhibited HA mRNA and protein expression while leaving other IAV mRNAs and proteins unaffected, and they also resulted in reduced IAV pathogenicity in mice. Thus, m 6 A residues in IAV transcripts enhance viral gene expression. [ABSTRACT FROM AUTHOR]