Huang Chenyang, Shu Xiao, Zhou Siting, Mi Yujie, Bian Hanxiao, Li Ting, Li Tengwei, Ying Xiner, Cheng Chongguang, Liu Donghong, Gao Minsong, Wen Yongjian, Ma Quan, Wang Fengqin, Cao Jie, Wang Jinkai, Liu Jianzhao
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China.
College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu, China.
Nat Chem Biol. 2025 May 22. doi: 10.1038/s41589-025-01900-9.
The precise location and functions of N-methyladenosine (mA) modification on mammalian nuclear noncoding RNA remain largely unknown. Here we developed nuclear-mA-label-seq to directly map human and mouse cell nuclear RNA mA methylome at single-base resolution. Specifically, mA modifications have been identified on abundant human γ satellite DNA II (GSATII) RNA transcripts, a type of repeat RNA, transcribed from SST1-TAR1-GSATII satellite arrays in the pericentromeric region of chromosome 9. GSATII RNA mA positively regulates the transcription of GSATII-located satellite arrays as well as trans-associated peri/centromeric satellites, typically chromosome 3 centromeric higher-order repeat α satellite. Dysregulation of this circuit renders a phenotype of abnormal chromosome segregation. Mechanistic study reveals that YTHDC1 reads GSATII RNA mA marks and recruits bromodomain protein 4 (BRD4) to promote transcriptions of the associated satellites via an mA-YTHDC1-BRD4-H3K27ac axis. These results uncover a mechanism governing the transcription of cis- and trans-associated pericentromeric and centromeric satellites via cross-talk between epitranscriptomic and epigenomic marks.
N-甲基腺苷（mA）修饰在哺乳动物细胞核非编码RNA上的精确位置和功能在很大程度上仍不清楚。在此，我们开发了细胞核mA标记测序技术，以单碱基分辨率直接绘制人类和小鼠细胞核RNA的mA甲基化组图谱。具体而言，已在丰富的人类γ卫星DNA II（GSATII）RNA转录本上鉴定到mA修饰，GSATII RNA转录本是一种重复RNA，由9号染色体着丝粒周围区域的SST1-TAR1-GSATII卫星阵列转录而来。GSATII RNA的mA正向调节位于GSATII的卫星阵列以及反式相关的着丝粒周围/着丝粒卫星（通常是3号染色体着丝粒高阶重复α卫星）的转录。该调控回路失调会导致染色体分离异常的表型。机制研究表明，YTHDC1识别GSATII RNA的mA标记并招募溴结构域蛋白4（BRD4），通过mA-YTHDC1-BRD4-H3K27ac轴促进相关卫星的转录。这些结果揭示了一种通过表观转录组和表观基因组标记之间的相互作用来调控顺式和反式相关着丝粒周围及着丝粒卫星转录的机制。
