Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Genet. 2022 Aug;54(8):1202-1213. doi: 10.1038/s41588-022-01119-7. Epub 2022 Jul 14.
Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone post-translational modifications, how DNA methylation is remodeled by oncogenic signaling remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancers. 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 the site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and disease.
表观遗传重塑对于癌基因诱导的细胞转化和恶性转化至关重要。与组蛋白翻译后修饰不同，癌基因信号如何重塑 DNA 甲基化仍知之甚少。癌蛋白 YAP 是 Hippo 信号转导中 TEAD 转录因子的共激活因子，在人类癌症中广泛激活。在这里，我们确定 5-甲基胞嘧啶双加氧酶 TET1 是 YAP 的直接靶标和主调控因子，可协调 YAP 靶基因在肝脏中的全基因组表观遗传和转录重编程。YAP 激活诱导 TET1 的表达，TET1 与 TEAD 物理相互作用导致 YAP 靶基因的局部 DNA 去甲基化、组蛋白 H3K27 乙酰化和染色质开放，从而促进转录激活。TET1 的缺失不仅逆转了 YAP 诱导的表观遗传和转录变化，而且抑制了 YAP 诱导的肝肿大和肿瘤发生。这些发现说明了致癌信号如何调节 DNA 去甲基化的位点特异性以促进肿瘤发生，并暗示 TET1 可能成为调节 YAP 信号在生理和疾病中的靶点。
