期刊
GENES & DEVELOPMENT
卷 28, 期 6, 页码 622-636出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.233239.113
关键词
histone methylation; Wnt signaling; Spindlin1; PRMT2; combinatorial readout
资金
- Major State Basic Research Development Program in China [2011CB965300]
- Program for New Century Excellent Talents in University
- National Natural Science Foundation of China, [31221064, 81272235]
- Major Science Programs of China [2011CB943803]
- Tsinghua-Peking Center for Life Sciences
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.
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