Zhang Lianjun, Lou Yidan, Li Weini, Guo Hongshan, Truong Nguyen Le Xuan, Chen Zhenhua
Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Zhejiang Provincial Key Laboratory of Hematopoietic Malignancy, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China.
Cell Investig. 2025 Jun;1(2). doi: 10.1016/j.clnves.2025.100023. Epub 2025 Jun 6.
The dedicated control of gene abundance is essential for both biological and pathological processes in mammals. Multiple layers of gene expression regulation, including transcriptional, post-transcriptional, translational, and post-translational regulation, collectively determine the highly dynamic equilibrium of functional protein abundance. Epigenetic modifications play indispensable roles in fine-tuning gene expression at either DNA, RNA, or protein level. To date, over 170 chemical modifications have been identified in RNA, with -methyladenosine (mA) emerging as the most abundant and functionally significant modification in messenger RNA (mRNA). Many proteins have been identified as mA-related proteins such as "writer" (deposition), "eraser" (removal) and "reader" (recognition). The dynamic mA abundance (controlled by writer and eraser) together with reader proteins determine mRNA fate/metabolism, including transcription, alternative splicing, nuclear export, mRNA stability, and translation. Here, we summarize the latest findings on mA-associated molecular mechanisms, emerging technologies for mapping mA, and the roles of mA-related proteins in both normal and malignant contexts. We further discuss/review the controversial opinions and open debates, and translational/clinical potential of mA/mA-related proteins as therapeutic targets, highlighting remaining questions and research directions in RNA mA modifications.
基因丰度的专门调控对于哺乳动物的生物学和病理过程都至关重要。基因表达调控的多个层面，包括转录、转录后、翻译和翻译后调控，共同决定了功能蛋白丰度的高度动态平衡。表观遗传修饰在DNA、RNA或蛋白质水平上对基因表达的微调中发挥着不可或缺的作用。迄今为止，在RNA中已鉴定出超过170种化学修饰，其中N6-甲基腺苷（m6A）成为信使RNA（mRNA）中最丰富且功能上最重要的修饰。许多蛋白质已被鉴定为与m6A相关的蛋白质，如“书写者”（沉积）、“擦除者”（去除）和“阅读者”（识别）。动态的m6A丰度（由书写者和擦除者控制）与阅读者蛋白共同决定mRNA的命运/代谢，包括转录、可变剪接、核输出、mRNA稳定性和翻译。在此，我们总结了关于m6A相关分子机制的最新发现、绘制m6A图谱的新兴技术，以及m6A相关蛋白在正常和恶性环境中的作用。我们进一步讨论/回顾了有争议的观点和公开辩论，以及m6A/m6A相关蛋白作为治疗靶点的转化/临床潜力，突出了RNA m6A修饰中仍存在的问题和研究方向。
