HDAC1/3-dependent moderate liquid-liquid phase separation of YY1 promotes METTL3 expression and AML cell proliferation.
Meng LiMingying LiYuan XiaGuosheng LiXiuhua SuDongmei WangJingjing YeFei LuTao SunChun-Yan JiPublished in: Cell death & disease (2022)
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.
Keyphrases
- acute myeloid leukemia
- poor prognosis
- transcription factor
- cell proliferation
- allogeneic hematopoietic stem cell transplantation
- histone deacetylase
- induced apoptosis
- signaling pathway
- binding protein
- cell cycle arrest
- long non coding rna
- gene expression
- high intensity
- acute lymphoblastic leukemia
- oxidative stress
- cell death
- weight loss
- single cell
- sensitive detection
- combination therapy
- fluorescent probe