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Developmental Cell|m⁶A去甲基化酶在胚胎发育和组织稳态中的生理意义N⁶-甲基腺苷(m⁶A)是最普遍的mRNA 修饰之一,m⁶A 修饰的动态变化由甲基转移酶(Writer)、去甲基化酶(Eraser)和阅读蛋白(Reader)等蛋白复合物共同调控。FTO 是主要的m⁶A 去甲基化酶之一,最初被认为可能与纤毛病和肥胖症有关联,然而其生理意义及潜在的作用机制仍然是一个悬而未决的问题。     

拟南芥m6A甲基化组的系统鉴定和功能分析

作为mRNA上最丰富的一种甲基化修饰,N⁶-甲基腺苷(N⁶-methyl-adenosine,m⁶A)广泛存在于酵母以及动植物中。然而多年来由于缺乏有效的技术手段,这些甲基化修饰发生在mRNA的什么位置,以及如何行使其生物学功能,却长时间没有定论。近年来,随着mRNA去甲基酶FTO和ALKBH5的发现,m⁶A被证明是一种动态可逆的甲基化修饰。人们意识到,mRNA上的m⁶A可能和多种生物学功能相关。最近,研究人员利用高通量测序的方法,系统鉴定出人和小鼠mRNA上m⁶A的修饰情况,揭示出这一修饰具有潜在的调控功能。随后,对YTH蛋白家族的研究表明,这类蛋白特异性的结合m⁶A位点,并介导mRNA的降解。     

m6A修饰与植物RNA病毒侵染

N⁶-甲基腺嘌呤(N6-methyladenosine, m⁶A)是真核生物m RNA中丰度最高的RNA转录后化学修饰. RNA的m⁶A修饰主要由甲基化转移酶(writers)、去甲基化酶(erasers)以及阅读蛋白(reader proteins)共同调控.近年的研究表明, m⁶A修饰在植物病毒侵染中发挥了重要作用,相关调控机制成为植物病毒领域的研究热点.本文概述了植物RNA m⁶A修饰相关蛋白的基本组成和m⁶A修饰的检测技术,重点阐述了m⁶A修饰在植物与RNA病毒互作中的作用,并提出了今后植物RNA病毒m⁶A修饰功能研究的方向.     

m6A修饰在植物生长发育和抗逆境胁迫中的功能

真核生物mRNA存在多种甲基化修饰,其中N⁶-腺苷酸甲基化(N⁶-methyladenosine, m⁶A)修饰是最为常见的一种动态内部修饰。m⁶A是指RNA腺嘌呤的第6位氮原子上发生甲基化修饰,它能够动态的被甲基转移酶添加,被去甲基化酶去除,以及被甲基化阅读蛋白识别。近年来,植物m⁶A修饰相关的酶被陆续鉴定,研究发现m⁶A修饰调控植物胚胎发育、茎尖分生组织分化、开花等生长发育过程,在植物抗逆境胁迫响应中也具有重要调控作用。本文就m⁶A修饰相关酶的组成及其在植物生长发育和植物抗逆境胁迫过程中的功能相关研究进展进行综述,并对甘蓝型油菜中m⁶A修饰相关的酶进行了生物信息学分析。     

m6A修饰在骨骼肌生成中的作用及骨骼肌损伤再生的中医疗法

骨骼肌是人体运动系统的主要器官,骨骼肌受损会降低生活质量、加重疾病恶化,探究骨骼肌再生和修复对恢复和维持肌肉功能至关重要。N6-甲基腺苷(N6-methyladenosine,m⁶A)修饰是真核生物中重要的mRNA甲基化修饰,其在调控骨骼肌生成中的作用与中医药健脾补肾法滋养肌肉生长相契合。本文总结了m⁶A甲基化修饰相关同源因子甲基转移酶、去甲基化酶和识别蛋白在骨骼肌生成中的作用,并探讨了其与中医理论的相关性,以及中医药疗法在骨骼肌生成中的应用,为深入研究骨骼肌修复与再生的相关分子机制及中医药介导m⁶A修饰调控骨骼肌生成提供理论依据和研究思路。     

m6A修饰对神经干细胞分化的影响

神经干细胞是中枢神经系统中具有自我更新能力并且能够分化产生成熟脑细胞的多潜能细胞，移植神经干细胞治疗神经退行性疾病是一项新兴趋势，已被证实可恢复疾病动物的神经功能。N⁶-甲基腺苷(N⁶-methyladenosine,m⁶A)发生在RNA分子腺苷酸第六位氮原子上，m⁶A甲基转移酶(Writers)和去甲基化酶(Erasers)能够可逆性调控RNA分子的m⁶A甲基化水平，而m⁶A甲基化结合蛋白(Readers)则可以识别RNA上的m⁶A修饰，影响RNA的降解、稳定性和翻译等生物学过程。研究表明，m⁶A修饰在神经系统中含量丰富，并且随着年龄的增长、疾病的进展，其水平发生改变。m⁶A相关酶表达的差异可引起m⁶A修饰水平的改变。一些神经相关因子受到m⁶A修饰的调控，在不改变碱基序列的条件下影响着神经干细胞的分化和神经系统功能的发挥。现将m⁶     

N6-甲基化腺嘌呤RNA甲基化修饰在中枢神经系统中的作用研究进展

mRNA存在多种转录后修饰,这些修饰调控mRNA的稳定和剪接、翻译、转运等多个过程,进而影响细胞发育、机体免疫、学习认知等重要生理功能。其中m⁶A修饰是转录后修饰中最丰富的一种,广泛存在于mRNA中,调控mRNA的代谢活动,影响基因表达。m⁶A修饰的稳态对神经系统的发育和功能维持至关重要。近年研究发现,在神经退行性疾病、精神疾病和脑肿瘤中均存在m⁶A修饰的身影。因此本文对近几年m⁶A甲基化修饰在中枢神经系统发育、功能及相关疾病中的作用进行总结,为神经系统疾病提供潜在的临床治疗靶点。     

RNA中6-甲基腺嘌呤的研究进展

RNA酶促共价修饰研究, 尤其是m⁶A(6-甲基腺嘌呤), 是RNA生物学研究的一个新兴领域。m⁶A是真核生物mRNA内部序列中最常见的一种转录后修饰形式, 由包含3个独立组分的复合物mRNA: m⁶A甲基转移酶催化生成。最新研究发现肥胖相关蛋白FTO可以脱掉m⁶A上的甲基, 表明该甲基化过程是可逆的。抑制或敲除m⁶A甲基转移酶会引起重要的表型变化, 但是由于过去的检测方法受限, m⁶A确切的作用机制目前为止还不甚清楚。二代测序技术结合免疫沉淀方法为大规模检测m⁶A修饰并研究其作用机制提供了可能。文章主要综述了m⁶A的发现史、生成机制、组织和基因组分布、检测方法、生物学功能等及其最新研究进展, 并通过比较3种IP-seq技术和数据分析的异同及优缺点, 对m⁶A这种RNA表观修饰研究中尚未解决的问题进行了讨论。     

RNA m6A甲基化与神经发育

中枢神经系统控制高级神经活动,例如知觉、运动、语言和认知等。作为人体神经系统最重要的部分,其正常的发育及功能活动在人体发育过程中至关重要。更好地了解调节神经系统发育的基本分子途径以及对大脑的基本生物学理解,可以帮助诊断和治疗各种神经疾病。RNA分子m⁶A修饰状态的动态变化及其功能主要由m⁶A甲基转移酶、m⁶A去甲基化酶和m⁶A阅读蛋白等蛋白质复合物共同调控。本文对此进行了详细介绍,并详细概述m⁶A修饰对神经发育的影响,重点介绍表观转录组学在基因调控中的作用。此外,还强调m⁶A修饰在神经发育过程中的生物学意义,包括神经发生、神经分化、轴突导向、突触形成及突触可塑性等。根据不同的实验原理和实验技术,本文详细介绍了最近发展的几种检测m⁶A位点的技术,每种方法都有各自的优点,据此将能够更广泛和更深入地研究这一修饰,并选择合适的方法去研究课题。RNA m⁶A甲基化是神经科学领域的一个新前沿。近年来,随着m⁶A检测技术的发展,m⁶A甲基化在神经系统发育过程中及神经疾病发生中的作用研究逐渐成为热点,具有很大潜力,为神经发育和神经疾病的研究提供了新视角。     

N6-腺苷酸甲基化修饰在脂质代谢紊乱疾病中调控作用研究进展

脂质代谢是一个复杂的生理过程,与营养调节、激素平衡和内分泌作用密切相关,它涉及多种因子和信号转导通路的互作。脂质代谢紊乱是诱发多种疾病的主要机制之一,如肥胖症、糖尿病、非酒精性脂肪肝病、肝炎、肝细胞癌及其并发症等。目前越来越多的研究发现RNA上发生的N⁶-腺苷酸甲基化(N⁶-adenylate methylation, m⁶A)“动态修饰”代表了一种全新的“转录后”调控方式,mRNA、tRNA、ncRNA等均可发生m⁶A修饰,m⁶A修饰异常调控基因表达变化和可变剪切事件发生。据最新文献报道,m⁶ARNA修饰参与了脂质代谢紊乱的表观遗传学调控。本文基于脂质代谢紊乱诱发的主要疾病,综述m⁶A修饰在其发生和发展中的调控作用。这些发现从表观遗传学的角度为进一步深入研究脂质代谢紊乱发病的潜在分子机制提供了依据,为相关疾病的卫生预防、分子诊断和治疗提供参考。     

Fat mass and obesity-associated protein regulates lipogenesis via m6A modification in fatty acid synthase mRNA

As the first identified N⁶-methyladenosine (m⁶A) demethylase, fat mass and obesity-associated (FTO) protein is associated with fatty acid synthase (FASN) and lipid accumulation. However, little is known about the regulatory role of FTO in the expression of FASN and de novo lipogenesis through m⁶A modification. In this study, we used FTO small interfering RNA to explore the effects of FTO knockdown on hepatic lipogenesis and its underlying epigenetic mechanism in HepG2 cells. We found that knockdown of FTO increased m⁶A levels in total RNA and enhanced the expression of YTH domain family member 2 which serves as the m⁶A-binding protein. The de novo lipogenic enzymes and intracellular lipid content were significantly decreased under FTO knockdown. Mechanistically, knockdown of FTO dramatically enhanced m⁶A levels in FASN messenger RNA (mRNA), leading to the reduced expression of FASN mRNA through m⁶A-mediated mRNA decay. The protein expressions of FASN along with acetyl CoA carboxylase and ATP-citrate lyase were further decreased, which inhibited de novo lipogenesis, thereby resulting in the deficiency of lipid accumulation in HepG2 cells and the induction of cellular apoptosis. The results reveal that FTO regulates hepatic lipogenesis via FTO-dependent m⁶A demethylation in FASN mRNA and indicate the critical role of FTO-mediated lipid metabolism in the survival of HepG2 cells. This study provides novel insights into a unique RNA epigenetic mechanism by which FTO mediates hepatic lipid accumulation through m⁶A modification and indicates that FTO could be a potential target for obesity-related diseases and cancer.     

FTO regulates adipogenesis by controlling cell cycle progression via m6A-YTHDF2 dependent mechanism

N⁶-methyladenosine (m⁶A) is the most prevalent internal mRNA modification in eukaryotes. Loss of m⁶A demethylase FTO increases m⁶A levels and inhibits adipogenesis of preadipocytes. However, its underlying mechanism remains elusive. Here, we demonstrated that silencing FTO inhibited adipogenesis of preadipocytes through impairing cell cycle progression at the early stage of adipogenesis. FTO knockdown markedly decreased the expression of CCNA2 and CDK2, crucial cell cycle regulators, leading to delayed entry of MDI-induced cells into G2 phase. Furthermore, the m⁶A levels of CCNA2 and CDK2 mRNA were significantly upregulated following FTO knockdown. m⁶A-binding protein YTHDF2 recognized and decayed methylated mRNAs of CCNA2 and CDK2, leading to decreased protein expression, thereby prolonging cell cycle progression and suppressing adipogenesis. Our work unravels that FTO regulates adipogenesis by controlling cell cycle progression in an m⁶A-YTHDF2 dependent manner, which provides insights into critical roles of m⁶A methylation in adipogenesis.     

The porcine fat mass and obesity associated (FTO) gene is associated with fat deposition in Italian Duroc pigs

In humans, common variants in the fat mass and obesity associated ( FTO ) gene are associated with body mass index and obesity. Here we sequenced exon 4, parts of introns 3 and 4 and two portions of the 3'-untranslated region of the porcine FTO gene in a panel of nine pigs of different breeds and identified three SNPs. Allele frequencies of the g.276T>G ( AM931150 ) mutation were studied in seven pig breeds. This mutation was used to linkage-map FTO to SSC6. Association analyses between the g.276T>G polymorphism and several traits [pH of semimembranosus muscle and estimated breeding values (EBV) for average daily gain, back fat thickness, lean cuts, ham weight and feed:gain ratio] were carried out in 257 sib-tested Italian Large White pigs. Only feed:gain ratio showed P  <   0.05. A selective genotyping approach was applied, analysing two extreme and divergent groups of Italian Large White pigs selected on the basis of back fat thickness EBV (50 with most positive and 50 with most negative values). Fisher's exact test (two-tailed) was not significant when comparing the allele frequencies of these two groups. The same approach was used in the Italian Duroc breed for which two extreme and divergent groups of animals were selected according to visible intermuscular fat EBV. Differences of allele frequencies between these two groups were highly significant ( P  <   0.00001, P  <   0.001 and P  <   0.0001, considering all animals or only two- or three-generation unrelated animals respectively), indicating association between the analysed FTO marker and intermuscular fat deposition.     

The role of RNA adenosine demethylases in the control of gene expression

RNA modifications are being recognized as an essential factor in gene expression regulation. They play essential roles in germ line development, differentiation and disease. In eukaryotic mRNAs, N⁶-adenosine methylation (m⁶A) is the most prevalent internal chemical modification identified to date. The m⁶A pathway involves factors called writers, readers and erasers. m⁶A thus offers an interesting concept of dynamic reversible modification with implications in fine-tuning the cellular metabolism. In mammals, FTO and ALKBH5 have been initially identified as m⁶A erasers. Recently, FTO m⁶A specificity has been debated as new reports identify FTO targeting N⁶,2′-O-dimethyladenosine (m⁶A_m). The two adenosine demethylases have diverse roles in the metabolism of mRNAs and their activity is involved in key processes, such as embryogenesis, disease or infection. In this article, we review the current knowledge of their function and mechanisms and discuss the existing contradictions in the field. This article is part of a Special Issue entitled: mRNA modifications in gene expression control edited by Dr. Soller Matthias and Dr. Fray Rupert.     

N~6 -methyl-adenosine (m ~6A) in RNA: An Old Modification with A Novel Epigenetic Function

N6 -methyl-adenosine (m6A) is one of the most common and abundant modifications on RNA molecules present in eukaryotes. However, the biological significance of m6A methylation remains largely unknown. Several independent lines of evidence suggest that the dynamic regulation of m6A may have a profound impact on gene expression regulation. The m6A modification is catalyzed by an unidentified methyltransferase complex containing at least one subunit methyltransferase like 3 (METTL3). m6A modification on messenger RNAs (mRNAs) mainly occurs in the exonic regions and 3’-untranslated region (3’-UTR) as revealed by high-throughput m6A-seq. One significant advance in m6A research is the recent discovery of the first two m6A RNA demethylases fat mass and obesity-associated (FTO) gene and ALKBH5, which catalyze m6A demethylation in an a-ketoglutarate (a-KG)-and Fe2+-dependent manner. Recent studies in model organisms demonstrate that METTL3, FTO and ALKBH5 play important roles in many biological processes, ranging from development and metabolism to fertility. Moreover, perturbation of activities of these enzymes leads to the disturbed expression of thousands of genes at the cellular level, implicating a regulatory role of m6A in RNA metabolism. Given the vital roles of DNA and histone methylations in epigenetic regulation of basic life processes in mammals, the dynamic and reversible chemical m6A modification on RNA may also serve as a novel epigenetic marker of profound biological significances.     

肥胖症易感基因——FTO的研究进展

FTO（fat mass and obesity associated）是肥胖症易感基因,表达于人体各组织,且在下丘脑中高表达。它能编码核酸去甲基化酶,通过去甲基化作用影响其他相关基因表达。FTO的基因多态性与体重指数（BMI）及肥胖症密切相关。FTO能够影响能量摄入及能量消耗,并通过多种途径诱导人群中肥胖症及2型糖尿病等相关疾病的发生,而FTO失活的小鼠能够避免肥胖发生。主要综述了FTO基因多态性与肥胖等疾病易感性的相关性、FTO可能的作用机制和FTO对人群中能量平衡的影响。     

N6-methyladenosine demethylase FTO promotes growth and metastasis of gastric cancer via m6A modification of caveolin-1 and metabolic regulation of mitochondrial dynamics

Gastric cancer (GC) is the fifth most common tumor and the third most deadly cancer worldwide. N6-methyladenosine (m⁶A) modification has been reported to play a regulatory role in human cancers. However, the exact role of m⁶A in GC remains largely unknown, and the dysregulation of m⁶A on mitochondrial metabolism has never been studied. In the present study, we demonstrated that FTO, a key demethylase for RNA m⁶A modification, was up-regulated in GC tissues, especially in tissues with liver metastasis. Functionally, FTO acted as a promoter for the proliferation and metastasis in GC. Moreover, FTO enhanced the degradation of caveolin-1 mRNA via its demethylation, which regulated the mitochondrial fission/fusion and metabolism. Collectively, our current findings provided some valuable insights into FTO-mediated m⁶A demethylation modification and could be used as a new strategy for more careful surveillance and aggressive therapeutic intervention.Subject terms: Cancer genomics, Gastrointestinal diseases