Nuclear m6A modification regulates satellite transcription and chromosome segregation

  • Nat Chem Biol. 2025 May 22. doi: 10.1038/s41589-025-01900-9.
Chenyang Huang  #  1 ,  Xiao Shu  #  1  2 ,  Siting Zhou  #  3  4 ,  Yujie Mi  1 ,  Hanxiao Bian  5 ,  Ting Li  1 ,  Tengwei Li  1 ,  Xiner Ying  1 ,  Chongguang Cheng  1 ,  Donghong Liu  1 ,  Minsong Gao  1 ,  Yongjian Wen  1 ,  Quan Ma  6 ,  Fengqin Wang  7 ,  Jie Cao  8  9 ,  Jinkai Wang  10  11 ,  Jianzhao Liu  12  13  14  15
Affiliations
  • 1. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China.
  • 2. College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology, Chengdu, China.
  • 3. Department of Medical Informatics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 4. Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, China.
  • 5. Laboratory of Fruit Quality Biology, Zhejiang Provincial Key Laboratory of Horticultural Plant Integrative Biology, Zhejiang University, Hangzhou, China.
  • 6. College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, China.
  • 7. College of Animal Sciences, Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, Zhejiang University, Hangzhou, China.
  • 8. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China. [email protected].
  • 9. Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 10. Department of Medical Informatics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 11. Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, China. [email protected].
  • 12. MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China. [email protected].
  • 13. Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 14. State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China. [email protected].
  • 15. Center for RNA Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China. [email protected].
  • # Contributed equally.
PMID: 40404899 DOI: 10.1038/s41589-025-01900-9
Abstract

The precise location and functions of N6-methyladenosine (m6A) modification on mammalian nuclear noncoding RNA remain largely unknown. Here we developed nuclear-m6A-label-seq to directly map human and mouse cell nuclear RNA m6A methylome at single-base resolution. Specifically, m6A 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 m6A 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 m6A marks and recruits bromodomain protein 4 (BRD4) to promote transcriptions of the associated satellites via an m6A-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.

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