The Roles of Hippo Signaling Transducers Yap and Taz in Chromatin Remodeling

Abstract

Hippo signaling controls cellular processes that ultimately impact organogenesis and homeostasis. Consequently, disease states including cancer can emerge when signaling is deregulated. The major pathway transducers Yap and Taz require cofactors to impart transcriptional control over target genes. Research into Yap/Taz-mediated epigenetic modifications has revealed their association with chromatin-remodeling complex proteins as a means of altering chromatin structure, therefore affecting accessibility and activity of target genes. Specifically, Yap/Taz have been found to associate with factors of the GAGA, Ncoa6, Mediator, Switch/sucrose nonfermentable (SWI/SNF), and Nucleosome Remodeling and Deacetylase (NuRD) chromatin-remodeling complexes to alter the accessibility of target genes. This review highlights the different mechanisms by which Yap/Taz collaborate with other factors to modify DNA packing at specific loci to either activate or repress target gene transcription.

Keywords: Hippo pathway; chromatin; epigenetic; transcription.

Figure 1

Yorkie interactions with the SWI/SNF complex. (A) Brahma and Yki–Sd interact to drive Drosophila midgut intestinal stem cell (ISC) proliferation. Notably, cotransfection with Hippo results in caspase-mediated proteolysis of Brahma and loss of complex stability. (B) Brahma has also been shown to interact with Yki–Sd at Yki target genes to promote tissue overgrowth in the wing disc and eye. This interaction occurred at the crumbs locus, providing evidence for a feed-forward loop of Crumbs-mediated Yki activation in regulation of tissue growth in Drosophila. (C) In the Drosophila wing imaginal disc, yki overexpression drives tissue overgrowth. This overgrowth phenotype was exacerbated by brahma knockdown, providing evidence for a regulatory role of Brahma in limiting Yki-mediated tissue overgrowth. Spacing of grey dots, representing nucleosomes, represents chromatin compaction.

Figure 2

YAP/TAZ interactions with the SWI/SNF complex. (A) BRM interaction with TAZ–TEAD at TAZ target loci drives transcription of genes specifying a basal cell fate in mammary epithelial cells (MECs). (B) The SWI/SNF subunit Brahma-associated factor 53a (BAF53A) interacts with p63 to inhibit the expression of WWC1/KIBRA. This results in the overactivation of YAP and is a hallmark of head and neck squamous cell carcinoma (HNSCC). (C) Direct interaction of the SWI/SNF subunit ARID1A with YAP/TAZ under conditions of low mechanical stimuli sequester YAP/TAZ from activating target gene expression. Under conditions of high mechanical stimuli, ARID1A itself is sequestered by nuclear F-actin, allowing YAP/TAZ to bind TEAD at target loci and induce transcription. Of note, interactions of YAP/TAZ with ARID1A does not alter chromatin accessibility at YAP/TAZ target loci. Spacing of grey dots, representing nucleosomes, represents chromatin compaction.

Figure 3

Yorkie interactions with GAF and the Mediator complex. Yki–Sd can interact with the chromatin protein GAF (A) or the Mediator complex subunit MED23 (B) to drive the transcription of Yki target genes that govern tissue proliferation. Although GAF and the Mediator complex do not contain intrinsic chromatin-remodeling capabilities, they are thought to recruit chromatin-remodeling proteins, yet to be identified, capable of modifying DNA organization.

Figure 4

Yorkie/YAP interactions with the histone methyltransferase (HMT) complex. (A) Ncoa6, a component of the Trithorax-related (Trr) H3K4 methyltransferase complex, binds to Yki–Sd and is capable of activating a Hippo response element (HRE) reporter in Drosophila. Ncoa6 interaction with Yki–Sd drives the expression of Yki target genes, inducing tissue growth and H3K4 methylation at these loci. (B) Human NCOA6 interaction with YAP–TEAD drives the expression of YAP target genes, providing evidence for evolutionary conservation between this Yki/YAP–HMT interaction.

Figure 5

YAP/TAZ/TEAD interactions with the NuRD complex. YAP/TAZ–TEAD bind targets and recruit the NuRD complex to repress target expression. This repression is mediated through dual ATP-dependent chromatin remodeling and histone deacetylase (HDAC)-mediated histone deacetylase functions of the NuRD complex to ultimately reduce chromatin accessibility. YAP/TAZ targets repressed by NuRD recruitment included genes that drive apoptosis and promote senescence.