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

• Published in: Nature communications 2024-05, Vol.15 (1), p.4322-4322, Article 4322
• Main Authors: Sun, Wenqi, Dong, Qianhua, Li, Xueqing, Gao, Jinxin, Ye, Xianwen, Hu, Chunyi, Li, Fei, Chen, Yong
• Format: Article
• Language: English
• Subjects: 14/63; 45/15; 45/22; 631/208/176/2016; 631/45/535/1266; 631/80/103/560; 82/16; 82/29; 82/80; 82/83; Binding; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Crystal structure; Crystallography, X-Ray; Epigenetics; Heterochromatin; Heterochromatin - metabolism; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histone H2A; Histones; Histones - metabolism; Humanities and Social Sciences; Liquid phases; Membrane proteins; multidisciplinary; Mutagenesis; Nuclear Envelope - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phase separation; Protein Binding; Proteins; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Schizosaccharomyces pombe Proteins - chemistry; Schizosaccharomyces pombe Proteins - genetics; Schizosaccharomyces pombe Proteins - metabolism; Science; Science (multidisciplinary); Telomere - genetics; Telomere - metabolism; Telomeres; Tethering; Yeasts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48418-7

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 Sad1 HBM 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. Here authors identify the interaction between the SUN-family protein Sad1 and histone H2A-H2B in S. pombe , and reveal the roles of the Sad1-histone interaction in the association of heterochromatin with the nuclear envelope and heterochromatin silencing.