Hippo signaling limits organ growth by inhibiting the transcriptional coactivator Yorkie. Despite the key role of Yorkie in both normal and oncogenic growth, the mechanism by which it activates transcription has not been defined. We report that Yorkie binding to chromatin correlates with histone H3K4 methylation and is sufficient to locally increase it. We show that Yorkie can recruit a histone methyltransferase complex through binding between WW domains of Yorkie and PPxY sequence motifs of NcoA6, a subunit of the Trithorax-related (Trr) methyltransferase complex. Cell culture and invivo assays establish that this recruitment of NcoA6 contributes to Yorkie's ability to activate transcription. Mammalian NcoA6, a subunit of Trr-homologous methyltransferase complexes, can similarly interact with Yorkie's mammalian homolog YAP. Our results implicate direct recruitment of a histone methyltransferase complex as central to transcriptional activation by Yorkie, linking the control of cell proliferation by Hippo signaling to chromatin modification.
Bibliographical noteFunding Information:
We thank Ali Shilatifard, the DSHB and the Bloomington Stock Center for antibodies and Drosophila stocks, and Flybase, Dibyendu Kumar, and the Waksman Genomics Core for bioinformatics and sequencing support. This research was supported by HHMI and NIH grants GM078620 (K.D.I.), 5R01GM054510 (R.S.M.), 5P50GM081892 (K.P.W.), and 3U01HG004264 (K.P.W.).
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