HDAC1/3-dependent moderate liquid-liquid phase separation of YY1 promotes METTL3 expression and AML cell proliferation.
HDAC1/3-dependent moderate liquid-liquid phase separation of YY1 promotes METTL3 expression and AML cell proliferation.
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DOI：
10.1038/s41419-022-05435-y
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发表时间：
2022-11-24
影响因子：
9
通讯作者：
Ji, Chunyan
中科院分区：
文献类型：
--
作者：
Li, Meng;Li, Mingying;Xia, Yuan;Li, Guosheng;Su, Xiuhua;Wang, Dongmei;Ye, Jingjing;Lu, Fei;Sun, Tao;Ji, Chunyan
甲基转移酶样蛋白3 （METTL3）在急性髓系白血病（AML）的进展中起着至关重要的作用，然而，METTL3在AML中异常过表达的机制尚不清楚。在目前的研究中，我们发现阴阳1 （YY1）作为转录因子结合到METTL3的启动子区域并促进其表达，从而增强AML细胞的增殖。在机制上，YY1与HDAC1/3结合，以适度的液-液相分离（LLPS）方式调节METTL3的表达。YY1的HDAC结合位点发生突变或HDAC抑制剂（HDACi）处理后，YY1与HDAC1/3分离，导致LLPS状态过度，从而抑制METTL3的表达和AML细胞的增殖。总之，我们的研究阐明了METTL3在AML中异常表达的调控机制，从LLPS度的角度揭示了YY1的精准“阴阳”调控机制，为AML的精准诊疗提供了新的思路。
Methyltransferase-like protein 3 (METTL3) plays critical roles in acute myeloid leukemia (AML) progression, however, the mechanism of abnormal overexpression of METTL3 in AML remain elusive. In the current study, we uncovered that Yin Yang 1 (YY1) binds to the promoter region of METTL3 as a transcription factor and promotes its expression, which in turn enhances the proliferation of AML cells. Mechanistically, YY1 binds to HDAC1/3 and regulates METTL3 expression in a moderate liquid-liquid phase separation (LLPS) manner. After mutation of the HDAC-binding site of YY1 or HDAC inhibitor (HDACi) treatment, YY1 was separated from HDAC1/3, which resulted in an excessive LLPS state, thereby inhibiting the expression of METTL3 and the proliferation of AML cells. In conclusion, our study clarified the regulatory mechanism of the abnormal expression of METTL3 in AML, revealed the precise “Yin-Yang” regulatory mechanism of YY1 from the perspective of LLPS degree, and provided new ideas for the precise diagnosis and treatment of AML.
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