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The SUN-family protein Sad1 mediates heterochromatin spatial organization through interaction with histone H2A-H2B

Author

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  • Wenqi Sun

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Qianhua Dong

    (New York University)

  • Xueqing Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jinxin Gao

    (New York University)

  • Xianwen Ye

    (University of Chinese Academy of Sciences
    100 Haike Road)

  • Chunyi Hu

    (National University of Singapore)

  • Fei Li

    (New York University)

  • Yong Chen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    100 Haike Road)

Abstract

Heterochromatin is generally associated with the nuclear periphery, but how the spatial organization of heterochromatin is regulated to ensure epigenetic silencing remains unclear. Here we found that Sad1, an inner nuclear membrane SUN-family protein in fission yeast, interacts with histone H2A-H2B but not H3-H4. We solved the crystal structure of the histone binding motif (HBM) of Sad1 in complex with H2A-H2B, revealing the intimate contacts between Sad1HBM and H2A-H2B. Structure-based mutagenesis studies revealed that the H2A-H2B-binding activity of Sad1 is required for the dynamic distribution of Sad1 throughout the nuclear envelope (NE). The Sad1-H2A-H2B complex mediates tethering telomeres and the mating-type locus to the NE. This complex is also important for heterochromatin silencing. Mechanistically, H2A-H2B enhances the interaction between Sad1 and HDACs, including Clr3 and Sir2, to maintain epigenetic identity of heterochromatin. Interestingly, our results suggest that Sad1 exhibits the histone-enhanced liquid-liquid phase separation property, which helps recruit heterochromatin factors to the NE. Our results uncover an unexpected role of SUN-family proteins in heterochromatin regulation and suggest a nucleosome-independent role of H2A-H2B in regulating Sad1’s functionality.

Suggested Citation

  • Wenqi Sun & Qianhua Dong & Xueqing Li & Jinxin Gao & Xianwen Ye & Chunyi Hu & Fei Li & Yong Chen, 2024. "The SUN-family protein Sad1 mediates heterochromatin spatial organization through interaction with histone H2A-H2B," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48418-7
    DOI: 10.1038/s41467-024-48418-7
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