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Peer-reviewedCC BY-NC-NDNature communications

Spatial partitioning of NSD2 defines H3K36me2 as an active mark for repetitive sequence activation.

  • Junqi Jia1,2
  • Yu Liu3
  • Jiamin Yu3
  • Jingwei Wang3
  • Yiting Zhang3
  • Yuan Fang3
  • Ying Yu4
  • Zhongxing Sun3
  • Zhuoning Li3
  • Yin Tang3
  • Juejia Shao3
  • Yanjun Zhang3
4 more authors
  • Hai Song3
  • Sergey V Ulianov5
  • Jing Huang4
  • Dong Fang6,7,8
8 affiliations
  1. 1Department of Hematology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
  2. 2Biological Laboratory of Hetao Cooperation Zone, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
  3. 3Life Sciences Institute, Zhejiang University, Hangzhou, China.
  4. 4State Key Laboratory of Oncogenes and Related Genes, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  5. 5Institute of Gene Biology, Moscow, Russia.
  6. 6Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  7. 7Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  8. 8Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou, China. [email protected].
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Abstract

Histone H3 lysine 36 dimethylation (H3K36me2) plays a key role in transcriptional elongation and chromatin organization, yet how its deposition is spatially controlled across the genome remains unclear. Here, we identify TOP1 as a critical recruiter of the H3K36me2 methyltransferase NSD2 to gene bodies. Disruption of the TOP1-NSD2 interaction reduces H3K36me2 at gene bodies, impairs RNA polymerase II release, and represses transcription. Remarkably, loss of this recruitment increases H3K36me2 at repetitive sequences, licensing their aberrant transcriptional activation. We show that NSD2 is primarily responsible for depositing H3K36me2 at these loci. We further identify MTA1 as a recruiter of NSD2 to repetitive elements via recognition of the GATC consensus sequence. Together, TOP1 and MTA1 spatially partition NSD2 across the genome, enabling H3K36me2 to serve dual roles in regulating canonical gene expression and acting as an active mark for the transcriptional activation of repetitive sequences.

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Cite

BibTeXRIS
BibTeX
@article{jia2026spatial,
  title = {{Spatial partitioning of NSD2 defines H3K36me2 as an active mark for repetitive sequence activation.}},
  author = {Junqi Jia and Yu Liu and Jiamin Yu and Jingwei Wang and Yiting Zhang and Yuan Fang and Ying Yu and Zhongxing Sun and Zhuoning Li and Yin Tang and Juejia Shao and Yanjun Zhang and Hai Song and Sergey V Ulianov and Jing Huang and Dong Fang},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77898-y},
  url = {https://europepmc.org/article/MED/42901929},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Spatial partitioning of NSD2 defines H3K36me2 as an active mark for repetitive sequence activation.
AU  - Junqi Jia
AU  - Yu Liu
AU  - Jiamin Yu
AU  - Jingwei Wang
AU  - Yiting Zhang
AU  - Yuan Fang
AU  - Ying Yu
AU  - Zhongxing Sun
AU  - Zhuoning Li
AU  - Yin Tang
AU  - Juejia Shao
AU  - Yanjun Zhang
AU  - Hai Song
AU  - Sergey V Ulianov
AU  - Jing Huang
AU  - Dong Fang
PY  - 2026
DA  - 2026/09/19
JO  - Nature communications
DO  - 10.1038/s41467-026-77898-y
UR  - https://europepmc.org/article/MED/42901929
AB  - Histone H3 lysine 36 dimethylation (H3K36me2) plays a key role in transcriptional elongation and chromatin organization, yet how its deposition is spatially controlled across the genome remains unclear. Here, we identify TOP1 as a critical recruiter of the H3K36me2 methyltransferase NSD2 to gene bodies. Disruption of the TOP1-NSD2 interaction reduces H3K36me2 at gene bodies, impairs RNA polymerase II release, and represses transcription. Remarkably, loss of this recruitment increases H3K36me2 at repetitive sequences, licensing their aberrant transcriptional activation. We show that NSD2 is primarily responsible for depositing H3K36me2 at these loci. We further identify MTA1 as a recruiter of NSD2 to repetitive elements via recognition of the GATC consensus sequence. Together, TOP1 and MTA1 spatially partition NSD2 across the genome, enabling H3K36me2 to serve dual roles in regulating canonical gene expression and acting as an active mark for the transcriptional activation of repetitive sequences.
SN  - 2041-1723
ER  -