Regulation of RNA stability plays a crucial role in gene expression control.Deadenylation is the initial rate-limiting step for the majority of RNA decay events.Here,we show that RING finger protein 219 (RNF219) interacts with the CCR4-NOT deadenylase complex.RNF219-CCR4-NOT exhibits deadenylation activity in vitro.RNA-seq analyses identify some of the 2-cell-specific genes and the neuronal genes significantly downregulated upon RNF219 knockdown,while upregulated after depletion of the CCR4-NOT subunit CNOT10 in mouse embryonic stem (ES) cells.RNF219 depletion leads to impaired neuronal lineage commitment during ES cell differentiation.Our study suggests that RNF219 is a novel interacting partner of CCR4-NOT and required for maintenance of ES cell pludpotency.