【《Nature Cell Biology》——促进急性髓系白血病的元凶之一：caRNA的m6A甲基化】
作者的研究结果表明RBFOX2可以识别染色质相关RNAs上的m6A，并招募RBM15、YTHDC1和PRC2来促进转录抑制，这一过程或许可以治疗白血病。

【题目】RBFOX2识别N6-甲基化腺苷以抑制转录并阻断髓系白血病分化

【摘要】N6-甲基腺苷 (m6A) 甲基化可通过 RNA 甲基转移酶复合物 (MTC)积累在染色质相关RNA（caRNA）上，以调节染色质的状态和转录。然而，MTC被招募到基因组不同位点的机制仍然难以确定。在本研究中，我们将一种已得到充分研究的RNA结合蛋白—RBFOX2确定为能够优先识别caRNA上m6A的染色质因子。RBFOX2可以招募MTC的一种组分RBM15，从而促进启动子相关RNAs的甲基化。RBM15还可以与YTHDC1发生物理性相互作用，将多梳抑制复合物2（PRC2）招募到RBFOX2结合位点上，以实现染色质沉默和转录抑制。此外，我们发现RBFOX2/m6A/RBM15/
YTHDC1/PRC2轴在髓系白血病中发挥着关键作用。下调RBFOX2可显著抑制急性髓系白血病细胞的存活和增殖，并促进其向髓系分化。白血病干细胞/起始细胞的自我更新和急性髓系白血病的维持需要RBFOX2参与。我们的研究显示m6A MTC募集和m6A在caRNA上堆积的途径，导致了染色质的位点选择性调节，这对白血病的治疗具有潜在的意义。

英文原文

[Report] Dou, Xiao, Shen, Wang et al. show that RBFOX2 recognizes m6A on chromatin-associated RNAs and recruits RBM15, YTHDC1 and PRC2 to facilitate transcription suppression. Inhibition of the axis exerts anti-leukaemic effects.

[Title] RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation

[Authors] Xiaoyang Dou, Yu Xiao, Chao Shen, Kitty Wang, Tong Wu, Chang Liu, Yini Li, Xianbin Yu, Jun Liu, Qing Dai, Kinga Pajdzik, Chang Ye, Ruiqi Ge, Boyang Gao, Jianhua Yu, Shuying Sun, Mengjie Chen, Jianjun Chen & Chuan He

[Abstract] N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, the mechanism by which MTC is recruited to distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as a chromatin factor that preferentially recognizes m6A on caRNAs. RBFOX2 can recruit RBM15, an MTC component, to facilitate methylation of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 and recruits polycomb repressive complex 2 (PRC2) to the RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis plays a critical role in myeloid leukaemia. Downregulation of RBFOX2 notably inhibits survival/proliferation of acute myeloid leukaemia cells and promotes their myeloid differentiation. RBFOX2 is also required for self-renewal of leukaemia stem/initiation cells and acute myeloid leukaemia maintenance. Our study presents a pathway of m6A MTC recruitment and m6A deposition on caRNAs, resulting in locus-selective chromatin regulation, which has potential therapeutic implications in leukaemia.

原文链接
http://t.cn/A6Oa3Cuu