Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Nat Genet. 2022 Sep;54(9):1427-1437. doi: 10.1038/s41588-022-01173-1. Epub 2022 Sep 7.
Transcriptional regulation, which integrates chromatin accessibility, transcription factors and epigenetic modifications, is crucial for establishing and maintaining cell identity. The interplay between different epigenetic modifications and its contribution to transcriptional regulation remains elusive. Here, we show that METTL3-mediated RNA N-methyladenosine (mA) formation leads to DNA demethylation in nearby genomic loci in normal and cancer cells, which is mediated by the interaction between mA reader FXR1 and DNA 5-methylcytosine dioxygenase TET1. Upon recognizing RNA mA, FXR1 recruits TET1 to genomic loci to demethylate DNA, leading to reprogrammed chromatin accessibility and gene transcription. Therefore, we have characterized a regulatory mechanism of chromatin accessibility and gene transcription mediated by RNA mA formation coupled with DNA demethylation, highlighting the importance of the crosstalk between RNA mA and DNA modification in physiologic and pathogenic process.
转录调控整合了染色质可及性、转录因子和表观遗传修饰，对于建立和维持细胞身份至关重要。不同表观遗传修饰之间的相互作用及其对转录调控的贡献仍然难以捉摸。在这里，我们表明 METTL3 介导的 RNA N6-甲基腺苷（m6A）形成导致正常和癌细胞中附近基因组位置的 DNA 去甲基化，这是由 m6A 读码器 FXR1 和 DNA 5-甲基胞嘧啶双加氧酶 TET1 之间的相互作用介导的。FXR1 一旦识别 RNA m6A，就会将 TET1 招募到基因组位置以实现 DNA 去甲基化，导致重新编程的染色质可及性和基因转录。因此，我们描述了一种由 RNA m6A 形成与 DNA 去甲基化偶联介导的染色质可及性和基因转录的调控机制，突出了 RNA m6A 和 DNA 修饰之间相互作用在生理和病理过程中的重要性。
