Major finding: YAP occupies a subset of highly active enhancers and regulates RNA Pol II pause release.
Mechanism: YAP recruits the mediator complex and CDK9 to chromatin, promoting YAP target gene transcription.
Impact: YAP binds to selected enhancers associated with critical growth genes important for tumorigenesis.
The Hippo pathway is an important regulator of cell growth and stem cell activity. When Hippo signaling is inactive, the transcriptional coactivator YAP and its paralogue TAZ translocate to the nucleus, where they bind TEAD transcription factors and regulate genes that result in increased organ size and tumorigenesis. Despite the importance of this pathway in cancer, the factors recruited by YAP/TAZ and TEADs and the binding sites of YAP/TAZ on chromatin remain largely unknown. Galli and colleagues used chromatin immunoprecipitation sequencing (ChIP-seq) in liver cancer cells to analyze the genome-wide occupancy of YAP, TEAD1, TEAD4, and TAZ, which revealed that YAP and TAZ have redundant occupancy patterns at a small subset of TEAD-bound distal regulatory enhancer elements. The YAP-bound enhancers were highly active with a higher density of activating histone marks than the average enhancer and high expression of the associated target genes. Twenty-five percent of the YAP-bound enhancers were classified as superenhancers (compared with only 2% of YAP-negative enhancers), and represent 17% of all superenhancers in the cell. YAP/TAZ was essential for the transcriptional output of these enhancers, with YAP/TAZ knockdown leading to loss of expression of the associated genes. YAP increased the transcriptional rate through the reduction of RNA polymerase II (Pol II) pausing, thereby enhancing transcriptional elongation. Mechanistically, YAP recruited the Mediator complex to target sites, allowing for the recruitment of the elongating kinase cyclin-dependent kinase 9 (CDK9), which controls transcriptional pause release and increases transcriptional activity. Silencing of Mediator or inhibition of CDK9 diminished YAP target gene expression and decreased YAP-driven growth and tumorigenesis. Taken together, these findings define the role of YAP at active distal enhancer regions in promoting RNA Pol II pause release and transcriptional elongation. These results may have clinical implications in YAP-driven tumors, which may benefit from transcriptional elongation inhibitors.
- ©2015 American Association for Cancer Research.
Volume 5, Issue 12
