Molecular basis underlying histone H3 lysine–arginine methylation pattern readout by Spin/Ssty repeats of Spindlin1
- Xiaonan Su1,2,6,
- Guixin Zhu1,3,6,
- Xiaozhe Ding1,2,
- Shirley Y. Lee4,
- Yali Dou4,
- Bing Zhu5,
- Wei Wu1,7 and
- Haitao Li1,2,7
- 1Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China;
- 2Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China;
- 3Tsinghua-Peking Center for Life Sciences, Beijing 100084, China;
- 4Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA;
- 5National Institute of Biological Sciences, Beijing 102206, China
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↵6 These authors contributed equally to this work.
Abstract
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/β-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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Footnotes
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↵7 Corresponding authors
E-mail lht{at}tsinghua.edu.cn
E-mail wwu{at}tsinghua.edu.cn
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.233239.113.
- Received October 17, 2013.
- Accepted January 30, 2014.
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