The CCR4–NOT complex maintains liver homeostasis through mRNA deadenylation

Abstract

The biological significance of deadenylation in global gene expression is not fully understood. Here, we show that the CCR4–NOT deadenylase complex maintains expression of mRNAs, such as those encoding transcription factors, cell cycle regulators, DNA damage response–related proteins, and metabolic enzymes, at appropriate levels in the liver. Liver-specific disruption of Cnot1, encoding a scaffold subunit of the CCR4–NOT complex, leads to increased levels of mRNAs for transcription factors, cell cycle regulators, and DNA damage response–related proteins because of reduced deadenylation and stabilization of these mRNAs. CNOT1 suppression also results in an increase of immature, unspliced mRNAs (pre-mRNAs) for apoptosis-related and inflammation-related genes and promotes RNA polymerase II loading on their promoter regions. In contrast, mRNAs encoding metabolic enzymes become less abundant, concomitant with decreased levels of these pre-mRNAs. Lethal hepatitis develops concomitantly with abnormal mRNA expression. Mechanistically, the CCR4–NOT complex targets and destabilizes mRNAs mainly through its association with Argonaute 2 (AGO2) and butyrate response factor 1 (BRF1) in the liver. Therefore, the CCR4–NOT complex contributes to liver homeostasis by modulating the liver transcriptome through mRNA deadenylation.

Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

“…In addition, enrichment of immune-related mRNAs among the upregulated mRNAs in Cnot3 βKO islets suggests an involvement of enhanced immune response in impaired β cells. It should be noted that enhanced immune response is observed in mouse tissues lacking CCR4–NOT complex function, such as liver and adipose tissues 16 , 18 , 55 , 63 . In our model, we cannot determine whether the increased immune response in Cnot3 βKO mice is a cause or a consequence of β-cell dysfunction.…”

The Regulatory Properties of the Ccr4–Not Complex

“…The expression of most mRNAs remains unchanged in these mice although there is an increase in mRNAs encoding energy metabolism related proteins [412]. A reduction in the level of metabolic enzymes has also been observed due to reduced pre-mRNAs in the absence of CNOT1, leading to hepatitis [414].…”

“…Disruption of the complex in the liver leads to loss of metabolic homeostasis, at least partially through an increase in level of FG21, a major regulator of whole-body metabolism [412][413][414]. CNOT3+/− mice tend to be lean with adipose and liver tissues containing reduced lipid levels and with increased metabolism [412].…”

Neuronal XRN1 is required for maintenance of whole-body metabolic homeostasis

“…Not surprisingly, deletion of mRNA degradation machinery leads to various physiological defects in animal models. For example, mutations in CCR4-NOT subunits in mouse cause defects in energy metabolism, adipocyte and heart function, and maturation of the liver and pancreatic β-cells ( Morita et al., 2011 ; Mostafa et al., 2020 ; Suzuki et al., 2019 ; Takahashi et al., 2015 , 2019 , 2020 ; Yamaguchi et al., 2018 ).…”