Active N6-Methyladenine demethylation by DMAD regulates gene expression by modulating the binding dynamics of Polycomb protein in neurons

A Ten-Eleven Translocation (TET) ortholog has been identified as a DNA N6-Methyladenine (6mA) demethylase (DMAD) in Drosophila. However, the molecular roles of 6mA and DMAD remain largely unexplored. Through genome-wide 6mA and transcriptome profiling, we found that 6mA may serve as a repressive epigenetic mark on a group of genes involved in neurodevelopment and neuronal functions. Mechanistically, DMAD coordinates with Trithorax-related complex protein Wds to maintain active transcription by dynamically demethylating intragenic 6mA. Accumulation of 6mA by depleting DMAD recruits Polycomb protein Pc as 6mA reader and contributes to transcriptional repression. Our findings define an epigenetic role for 6mA and suggest that active 6mA demethylation by DMAD plays important roles in fly CNS function by coordinating additional epigenetic mechanisms. Examine the role of DMAD and 6mA DNA modification in Drosophila neuronal functions

已有研究在果蝇（Drosophila）中鉴定出十十一易位（Ten-Eleven Translocation, TET）同源蛋白为DNA N6-甲基腺嘌呤（DNA N6-Methyladenine, 6mA）去甲基化酶（DMAD）。然而，6mA与DMAD的分子功能仍未得到充分解析。本研究通过全基因组6mA修饰与转录组联合分析，发现6mA可作为一类参与神经发育及神经元功能的基因的抑制性表观遗传标记。机制层面，DMAD可与三胸相关复合物蛋白Wds协同，通过动态去除基因内区域的6mA修饰以维持靶基因的活跃转录。敲除DMAD会导致果蝇体内6mA累积，此时6mA可作为修饰识别蛋白招募多梳蛋白（Polycomb protein, Pc），进而介导转录抑制过程。本研究明确了6mA的表观遗传调控功能，并揭示DMAD介导的主动6mA去甲基化可通过协同其他表观遗传机制，在果蝇中枢神经系统（CNS）功能中发挥关键作用。本研究核心为探究DMAD与6mA DNA修饰在果蝇神经元功能中的调控作用。