Nuclear m6A modification regulates satellite transcription and chromosome segregation PMID: 40404899

ADC Targets in Oncology

2026-04-10

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.

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.