Abstract
RNA binding proteins (RBPs)-mediated post-transcriptional control has been implicated in influencing various aspects of RNA metabolism and playing important roles in mammalian development and pathological diseases. However, the functions of specific RBPs and the molecular mechanisms through which they act in monocyte/macrophage differentiation remain to be determined. In this study, through bioinformatics analysis and experimental validation, we identify that ZFP36L1, a member of ZFP36 zinc finger protein family, exhibits significant decrease in acute myeloid leukemia (AML) patients compared with normal controls and remarkable time-course increase during monocyte/macrophage differentiation of PMA-induced THP-1 and HL-60 cells as well as induction culture of CD34+ hematopoietic stem/progenitor cells (HSPCs). Lentivirus-mediated gain and loss of function assays demonstrate that ZFP36L1 acts as a positive regulator to participate in monocyte/macrophage differentiation. Mechanistic investigation further reveals that ZFP36L1 binds to the CDK6 mRNA 3′untranslated region bearing adenine-uridine rich elements and negatively regulates the expression of CDK6 which is subsequently demonstrated to impede the in vitro monocyte/macrophage differentiation of CD34+ HSPCs. Collectively, our work unravels a ZFP36L1-mediated regulatory circuit through repressing CDK6 expression during monocyte/macrophage differentiation, which may also provide a therapeutic target for AML therapy.
Highlights
RNA binding proteins (RBPs)-mediated post-transcriptional control has been implicated in influencing various aspects of RNA metabolism and playing important roles in mammalian development and pathological diseases
Through bioinformatics analysis and subsequent experimental validation, we found that ZFP36L1 expression was aberrantly decreased in acute myeloid leukemia (AML) patients compared with normal controls and selectively up-regulated during monocyte/macrophage differentiation and facilitated the process by directly binding to AREs in the 3′ untranslated regions (UTRs) of CDK6 mRNA, leading to decreased expression of CDK6, which unravels a RBP-mediated regulatory circuit composed of ZFP36L1 and CDK6 and provides a potential target for AML therapy
To systematically screen the RBPs involved in myeloid differentiation, we performed bioinformatics analysis using the expression profiling data of AML patients (GSE30285 and GSE34184) and in vitro myeloid differentiation from hematopoietic stem/progenitor cells (HSPCs) (GSE12803 and GSE24759) annotated in the GEO DataSets
Summary
RNA binding proteins (RBPs)-mediated post-transcriptional control has been implicated in influencing various aspects of RNA metabolism and playing important roles in mammalian development and pathological diseases. The process is elaborately controlled by a complex regulatory network including RBPs. Over-expression of ZFP36L1 and ZFP36 in CD34+ hematopoietic progenitors impairs erythroid differentiation by mediating stat5b mRNA degradation through binding to its 3′ UTR25. Through bioinformatics analysis and subsequent experimental validation, we found that ZFP36L1 expression was aberrantly decreased in acute myeloid leukemia (AML) patients compared with normal controls and selectively up-regulated during monocyte/macrophage differentiation and facilitated the process by directly binding to AREs in the 3′ UTR of CDK6 mRNA, leading to decreased expression of CDK6, which unravels a RBP-mediated regulatory circuit composed of ZFP36L1 and CDK6 and provides a potential target for AML therapy
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