The Hippo effector Yorkie activates transcription by interacting with a histone methyltransferase complex through Ncoa6

Abstract

The Hippo signaling pathway regulates tissue growth in Drosophila through the transcriptional coactivator Yorkie (Yki). How Yki activates target gene transcription is poorly understood. Here, we identify Nuclear receptor coactivator 6 (Ncoa6), a subunit of the Trithorax-related (Trr) histone H3 lysine 4 (H3K4) methyltransferase complex, as a Yki-binding protein. Like Yki, Ncoa6 and Trr are functionally required for Hippo-mediated growth control and target gene expression. Strikingly, artificial tethering of Ncoa6 to Sd is sufficient to promote tissue growth and Yki target expression even in the absence of Yki, underscoring the importance of Yki-mediated recruitment of Ncoa6 in transcriptional activation. Consistent with the established role for the Trr complex in histone methylation, we show that Yki, Ncoa6, and Trr are required for normal H3K4 methylation at Hippo target genes. These findings shed light on Yki-mediated transcriptional regulation and uncover a potential link between chromatin modification and tissue growth.DOI: http://dx.doi.org/10.7554/eLife.02564.001

The cancer COMPASS: navigating the functions of MLL complexes in cancer

“…NCOA6 is a common coactivator (107) and has been demonstrated to be essential for embryo development and survival through knock-out studies in mice (108e110). The Drosophila NcoA6 gene has also been shown to be important for viability and proper tissue development through interaction with the Yorkie/YAP transcriptional activator involved in the Hippo signaling pathway (111,112). NCOA6 has been shown to associate with a large variety of nuclear hormone receptors, including prostanoid, retinoid, vitamin D3, thyroid hormone, and steroid receptors in humans, enhancing the activating ability of these transcription factors.…”

Mechanisms of Hippo pathway regulation

“…Many genes are transcriptionally activated by TEAD complexed with YAP and/or TAZ (Zhu et al 2015). Mechanistically, YAP and TAZ stimulate TEAD transcriptional activity by recuriting components of the SWI/SNF chromatin remodeling complex or NCOA6 histone methyltransferase complex (Oh et al 2013(Oh et al , 2014Qing et al 2014;Skibinski et al 2014). Interestingly, the YAP/TAZ-TEAD complex can also operate as transcriptional corepressors by recruiting the NuRD histone deacetylate complex for additional target genes, such as DDIT4 and Trail regulation.…”

The regulation and function of YAP transcription co-activator

“…Back in 2005, it was proposed that TAZ can associate with histone acetyltransferases p300 and PCAF, and dramatically activates TBX5-dependent promoters, but whether YAP has the same activity has not been confirmed [118]. Moreover, it was recently reported that Yki regulates transcription through WW domain-mediated interaction with NcoA6 (a subunit of the Trr methyltransferase complex) and then modification of local chromatin [145,146]. NcoA6 is required for Yki/Sd-induced tissue overgrowth.…”