Molecular basis underlying histone H3 lysine-arginine methylation pattern readout by Spin/Ssty repeats of Spindlin1

作者：Su, Xiaonan; Zhu, Guixin; Ding, Xiaozhe; Lee, Shirley Y.; Dou, Yali; Zhu, Bing; Wu, Wei^*; Li, Haitao

来源：Genes & Development, 2014, 28(6): 622-636.

DOI：10.1101/gad.233239.113

• histone methylation
• Wnt signaling
• Spindlin1
• PRMT2
• combinatorial readout

Histone modification patterns and their combinatorial readout have emerged as a fundamental mechanism for epigenetic regulation. Here we characterized Spindlin1 as a histone effector that senses a cis-tail histone H3 methylation pattern involving trimethyllysine 4 (H3K4me3) and asymmetric dimethylarginine 8 (H3R8me2a) marks. Spindlin1 consists of triple tudor-like Spin/Ssty repeats. Cocrystal structure determination established concurrent recognition of H3K4me3 and H3R8me2a by Spin/Ssty repeats 2 and 1, respectively. Both H3K4me3 and H3R8me2a are recognized using an "insertion cavity'' recognition mode, contributing to a methylation state-specific layer of regulation. In vivo functional studies suggest that Spindlin1 activates Wnt/beta-catenin signaling downstream from protein arginine methyltransferase 2 (PRMT2) and the MLL complex, which together are capable of generating a specific H3 "K4me3-R8me2a'' pattern. Mutagenesis of Spindlin1 reader pockets impairs activation of Wnt target genes. Taken together, our work connects a histone "lysine-arginine'' methylation pattern readout by Spindlin1-to-Wnt signaling at the transcriptional level.

• 出版日期2014-3-15
• 单位北京生命科学研究所; 清华大学