RNA m⁶A modification: a key regulator in normal and malignant processes

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 N ⁶-methyladenosine (m⁶A) emerging as the most abundant and functionally significant modification in messenger RNA (mRNA). Many proteins have been identified as m⁶A-related proteins such as "writer" (deposition), "eraser" (removal) and "reader" (recognition). The dynamic m⁶A 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 m⁶A-associated molecular mechanisms, emerging technologies for mapping m⁶A, and the roles of m⁶A-related proteins in both normal and malignant contexts. We further discuss/review the controversial opinions and open debates, and translational/clinical potential of m⁶A/m⁶A-related proteins as therapeutic targets, highlighting remaining questions and research directions in RNA m⁶A modifications.