Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing Methylation profiling by high throughput sequencing
Summary
Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone posttranslational modification, how oncogenic signaling remodels DNA methylation remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancer. Here we identify the 5-methylcytosine dioxygenase TET1 as a direct YAP target and a master regulator that coordinates the genome-wide epigenetic and transcriptional reprogramming of YAP target genes in the liver. YAP activation induces the expression of TET1, which physically interacts with TEAD to cause regional DNA demethylation, histone H3K27 acetylation and chromatin opening in YAP target genes to facilitate transcriptional activation. Loss of TET1 not only reverses YAP-induced epigenetic and transcriptional changes but also suppresses YAP-induced hepatomegaly and tumorigenesis. These findings exemplify how oncogenic signaling regulates site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and diseases.
Overall design
liver mRNA profiles of doxycycline treated control, YAP transgenic, Tet1 KO YAP transgenic mice and decitabine treated Tet1 KO YAP transgenic mice
methylated DNA were collected with Methylminer kits. TEAD and TET1 associated DNA fragment were collected with specific antibody as described
Less...
More...