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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.

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