The Myb-MuvB Complex Is Required for YAP-Dependent Transcription of Mitotic Genes

• Published in: Cell reports (Cambridge) 2019-06, Vol.27 (12), p.3533-3546.e7
• Main Authors: Pattschull, Grit, Walz, Susanne, Gründl, Marco, Schwab, Melissa, Rühl, Eva, Baluapuri, Apoorva, Cindric-Vranesic, Anita, Kneitz, Susanne, Wolf, Elmar, Ade, Carsten P., Rosenwald, Andreas, von Eyss, Björn, Gaubatz, Stefan
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; Animals; B-MYB; Breast - cytology; Breast - metabolism; Cell Cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cells, Cultured; Chromatin - genetics; Chromatin - metabolism; enhancer; Enhancer Elements, Genetic; Female; Gene Expression Regulation; Humans; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mitosis - genetics; mitotic genes; Myb-MuvB; Prognosis; Promoter Regions, Genetic; Survival Rate; Trans-Activators - genetics; Trans-Activators - metabolism; transcription; Transcription Factors - genetics; Transcription Factors - metabolism; YAP
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.05.071

YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways. [Display omitted] •YAP induces the expression and chromatin binding of the Myb-MuvB subunit B-MYB•YAP interacts with B-MYB-regulated promoters from distant enhancers•B-MYB is required for YAP-mediated expression of mitotic genes•The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, Pattschull et al. show that YAP induces the expression of the MMB subunit B-MYB and promotes the binding of B-MYB to the promoters of G2/M genes from distant enhancers, leading to the enhanced expression of mitotic genes.