N6-甲基化腺苷修饰在乳腺癌中的研究进展

表观遗传学在乳腺癌的恶性进展中起到重要作用,其中N⁶-甲基化腺苷(m⁶A)修饰是最丰富的RNA修饰,参与调节乳腺癌细胞恶性行为的通路及癌细胞所处的肿瘤微环境。同时,乳腺癌发病率居于我国女性恶性肿瘤首位,近年来首次发病年龄趋于年轻化,是严重危及我国女性健康的疾病之一。然而,乳腺癌早期治疗预后较好。当晚期出现转移后,患者5年生存率差。m⁶A作为一种可能用于乳腺癌早筛的生物标志物及新的药物治疗靶点,给乳腺癌的早期治疗提供了新的研究方向。本文系统地综述了m⁶A修饰相关因子及其在乳腺癌恶性行为中发挥的调控作用,并列出现已知的一些靶向药物和潜在的早筛方法,为乳腺癌的诊断、治疗、监测提供新的思路。     

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.     

RNA m6A修饰在肿瘤发展及免疫治疗中的研究进展

N6-甲基腺嘌呤(N6-methyladenosine,m⁶A)是指在腺苷的N6位置发生的甲基化修饰,是真核m RNA中最常见的表观遗传修饰方式。m⁶A甲基化的紊乱会导致基因转录和翻译过程异常,从而促进癌症的发生和发展。最近的研究表明,m⁶A甲基化不仅可以影响肿瘤的细胞增殖和抑制信号网络,还能调节肿瘤免疫原性。该研究聚焦于探讨m⁶A调节因子在调控肿瘤关键信号通路中的相关机制,并阐述了m⁶A表观遗传修饰调节免疫检查点的表达方式。这将为理解m⁶A表观遗传修饰在调节肿瘤免疫逃逸中的作用和机制提供一个新的思路。此外,该文还强调了基于m⁶A修饰的靶向联合免疫治疗策略的前景和发展方向,这有望提高免疫检查点抑制剂的治疗效果。     

m6A修饰调控细胞自噬参与雄性生殖疾病研究进展

N⁶-甲基腺苷(N⁶-methyladenosine, m⁶A)修饰是在腺苷核苷酸N⁶位置上发生的甲基化,在多种RNA代谢过程如m RNA剪接、翻译、运输、降解中发挥关键作用,进而对各种生命过程产生广泛影响。细胞自噬是真核细胞在自噬相关基因的调控下通过溶酶体对自身细胞质蛋白质和受损细胞器进行降解的过程。本文总结了m⁶A修饰调控细胞自噬在雄性生殖疾病发生发展过程中的研究进展,旨在为今后m⁶A修饰调节自噬水平在雄性生殖中的调控机理研究提供参考资料,为雄性生殖疾病的治疗策略提供新方向。     

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。     

N6-甲基腺苷修饰对女性生殖系统功能的影响

近年来女性不孕不育率不断攀升，已成为我国提高生育率亟需解决的困境。生殖系统的健康是保证生育能力的前提条件。N ⁶-甲基腺苷(N⁶-methyladenosine,m⁶A)是真核生物中最常见的化学修饰，在细胞生命活动中发挥着极其重要的作用。近来，m⁶A修饰被证实在女性生殖系统的各种生理和病理过程中起着关键作用，但其调控机制及生物学功能仍不清楚。本文首先介绍了m⁶A修饰的可逆调节机制及其功能，随后讨论了其在女性生殖功能和生殖系统疾病中的作用，最后对m⁶A修饰的检测技术和方法及其最新进展进行了归纳总结，以期为后续女性生殖系统发病机制和治疗研究提供参考。     

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-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。     

m6A修饰在肝纤维化中的研究进展

N⁶-甲基腺苷(N⁶-methyladenosine,m⁶A)作为真核生物中最丰富的RNA内部修饰,影响RNA的加工,调节mRNA翻译效率,并与多种表观遗传学机制发生交互作用,进而在多种生理过程中调控基因的表达。肝纤维化是细胞外基质(extracellular matrix,ECM)蛋白(主要是Ⅰ型和Ⅲ型胶原蛋白)积累形成的纤维瘢痕取代正常组织的过程,是肝脏对慢性损伤的病理性修复反应。m⁶A修饰直接参与肝细胞损伤、炎症细胞募集和肝星状细胞激活等肝纤维化过程,并通过降低HBV蛋白的表达、与微RNA (microRNA)和肠道菌群相互作用等途径间接影响肝纤维化的发生发展。由于肝脏的再生能力较强,当慢性炎症或肝损伤的主要病因去除后,早期已经发生纤维化的肝脏可逆转为正常肝脏。m⁶A修饰在肝纤维化中的双重作用可为平衡机体纤维化过程提供思路。该文综述了m⁶A修饰在肝纤维化中的功能和作用机制,以期为相关疾病的诊疗提供新的思路。     

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。     

Novel insights into m6A modification of coding and non-coding RNAs in tumor biology: From molecular mechanisms to therapeutic significance

Accumulating evidence has revealed that m⁶A modification, the predominant RNA modification in eukaryotes, adds a novel layer of regulation to the gene expression. Dynamic and reversible m⁶A modification implements sophisticated and crucial functions in RNA metabolism, including generation, splicing, stability, and translation in messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs). Furthermore, m⁶A modification plays a determining role in producing various m⁶A-labeling RNA outcomes, thereby affecting several functional processes, including tumorigenesis and progression. Herein, we highlighted current advances in m⁶A modification and the regulatory mechanisms underlying mRNAs and ncRNAs in distinct cancer stages. Meanwhile, we also focused on the therapeutic significance of m⁶A regulators in clinical cancer treatment.     

The detection and functions of RNA modification m6A based on m6A writers and erasers

N⁶-methyladenosine (m⁶A) is the most frequent chemical modification in eukaryotic mRNA and is known to participate in a variety of physiological processes, including cancer progression and viral infection. The reversible and dynamic m⁶A modification is installed by m⁶A methyltransferase (writer) enzymes and erased by m⁶A demethylase (eraser) enzymes. m⁶A modification recognized by m⁶A binding proteins (readers) regulates RNA processing and metabolism, leading to downstream biological effects such as promotion of stability and translation or increased degradation. The m⁶A writers and erasers determine the abundance of m⁶A modifications and play decisive roles in its distribution and function. In this review, we focused on m⁶A writers and erasers and present an overview on their known functions and enzymatic molecular mechanisms, showing how they recognize substrates and install or remove m⁶A modifications. We also summarize the current applications of m⁶A writers and erasers for m⁶A detection and highlight the merits and drawbacks of these available methods. Lastly, we describe the biological functions of m⁶A in cancers and viral infection based on research of m⁶A writers and erasers and introduce new assays for m⁶A functionality via programmable m⁶A editing tools.     

The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation

Ribosomal RNAs (rRNAs) have long been known to carry chemical modifications, including 2′O-methylation, pseudouridylation, N⁶-methyladenosine (m⁶A), and N^6,6-dimethyladenosine. While the functions of many of these modifications are unclear, some are highly conserved and occur in regions of the ribosome critical for mRNA decoding. Both 28S rRNA and 18S rRNA carry single m⁶A sites, and while the methyltransferase ZCCHC4 has been identified as the enzyme responsible for the 28S rRNA m⁶A modification, the methyltransferase responsible for the 18S rRNA m⁶A modification has remained unclear. Here, we show that the METTL5-TRMT112 methyltransferase complex installs the m⁶A modification at position 1832 of human 18S rRNA. Our work supports findings that TRMT112 is required for METTL5 stability and reveals that human METTL5 mutations associated with microcephaly and intellectual disability disrupt this interaction. We show that loss of METTL5 in human cancer cell lines and in mice regulates gene expression at the translational level; additionally, Mettl5 knockout mice display reduced body size and evidence of metabolic defects. While recent work has focused heavily on m⁶A modifications in mRNA and their roles in mRNA processing and translation, we demonstrate here that deorphanizing putative methyltransferase enzymes can reveal previously unappreciated regulatory roles for m⁶A in noncoding RNAs.     

Downregulation of m6A Reader YTHDC2 Promotes the Proliferation and Migration of Malignant Lung Cells via CYLD/NF-κB Pathway

Lung cancer is one of the most common types of carcinoma worldwide. Cigarette smoking is considered the leading cause of lung cancer. Aberrant expression of several YT521-B homology (YTH) family proteins has been reported to be closely associated with multiple cancer types. The present study aims to evaluate the function and regulatory mechanisms of the N6-methyladenosine (m⁶A) reader protein YTH domain containing 2 (YTHDC2) by in vitro, in vivo and bioinformatics analyses. The results revealed that YTHDC2 was reduced in lung cancer and cigarette smoke-exposed cells. Notably, bioinformatics and tissue arrays analysis demonstrated that decreased YTHDC2 was highly associated with smoking history, pathological stage, invasion depth, lymph node metastasis and poor outcomes. The in vivo and in vitro studies revealed that YTHDC2 overexpression inhibited the proliferation and migration of lung cancer cells as well as tumor growth in nude mice. Furthermore, YTHDC2 decreased expression was modulated by copy number deletion in lung cancer. Importantly, the cylindromatosis (CYLD)/NF-κB pathways were confirmed as the downstream signaling of YTHDC2, and this axis was mediated by m⁶A modification. The present results indicated that smoking-related downregulation of YTHDC2 was associated with enhanced proliferation and migration in lung cancer cells, and appeared to be regulated by DNA copy number variation. Importantly, YTHDC2 functions as a tumor suppressor through the CYLD/NF-κB signaling pathway, which is mediated by m⁶A modification.     

Regulation of Virus Replication and T Cell Homeostasis by N~6-Methyladenosine

RNA modifications are abundant in eukaryotes, bacteria, and archaea. N~6-methyladenosine(m~6A), a type of RNA modification mainly found in messenger RNA(mRNA), has significant effects on the metabolism and function of m RNAs. This modification is governed by three types of proteins, namely methyltransferases as ‘‘writers' ', demethylases as ‘‘erasers' ',and specific m~6A-binding proteins(YTHDF1-3) as ‘‘readers' '. Further, it is important for the regulation of cell fate and has a critical function in many biological processes including virus replication, stem cell differentiation, and cancer development, and exerts its effect by controlling gene expression. Herein, we summarize recent advances in research on m~6A in virus replication and T cell regulation, which is a rapidly emerging field that will facilitate the development of antiviral therapies and the study of innate immunity.