Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Huashan Hospital and Key Laboratory of Medical Epigenetics and Metabolism and Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Medical College of Xiamen University, Xiamen 361102, China.
Cell Rep. 2018 Nov 6;25(6):1485-1500.e4. doi: 10.1016/j.celrep.2018.10.028.
The TET2 DNA dioxygenase regulates gene expression by catalyzing demethylation of 5-methylcytosine, thus epigenetically modulating the genome. TET2 does not contain a sequence-specific DNA-binding domain, and how it is recruited to specific genomic sites is not fully understood. Here we carried out a mammalian two-hybrid screen and identified multiple transcriptional regulators potentially interacting with TET2. The SMAD nuclear interacting protein 1 (SNIP1) physically interacts with TET2 and bridges TET2 to bind several transcription factors, including c-MYC. SNIP1 recruits TET2 to the promoters of c-MYC target genes, including those involved in DNA damage response and cell viability. TET2 protects cells from DNA damage-induced apoptosis dependending on SNIP1. Our observations uncover a mechanism for targeting TET2 to specific promoters through a ternary interaction with a co-activator and many sequence-specific DNA-binding factors. This study also reveals a TET2-SNIP1-c-MYC pathway in mediating DNA damage response, thereby connecting epigenetic control to maintenance of genome stability.
TET2 DNA 双加氧酶通过催化 5-甲基胞嘧啶的去甲基化来调节基因表达，从而对基因组进行表观遗传调节。TET2 不含有序列特异性的 DNA 结合结构域，其如何被招募到特定的基因组位点尚不完全清楚。在这里，我们进行了哺乳动物双杂交筛选，鉴定出多个可能与 TET2 相互作用的转录调节因子。SMAD 核相互作用蛋白 1（SNIP1）与 TET2 发生物理相互作用，并将 TET2 桥接到多个转录因子上，包括 c-MYC。SNIP1 将 TET2 招募到 c-MYC 靶基因的启动子上，这些基因包括参与 DNA 损伤反应和细胞存活的基因。TET2 通过 SNIP1 依赖的方式保护细胞免受 DNA 损伤诱导的凋亡。我们的观察结果揭示了一种通过与共激活因子和许多序列特异性 DNA 结合因子的三元相互作用将 TET2 靶向特定启动子的机制。本研究还揭示了 TET2-SNIP1-c-MYC 通路在介导 DNA 损伤反应中的作用，从而将表观遗传调控与基因组稳定性的维持联系起来。
