The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation.

Akiko Yanagiya,Shou Soeda,Mayo Shigeta,Haytham Mohamed Aly Mohamed,Tadashi Yamamoto,Toru Suzuki,Shungo Kobori,Shohei Takaoka,Yasuhide Furuta,Akinori Takahashi,Takaya Abe,Tomokazu Yamaguchi,Keiji Kuba

doi:10.26508/lsa.201900494

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.

Highlights

In mammals, the liver is essential to control energy intake and expenditure so as to maintain organismal energy homeostasis
Homozygous Cnot1-KO (Cnot1−/−) mice were not obtained after embryonic day 8.5, indicating that Cnot1−/− mice die in embryo (Fig S1E)
MRNAs expressed at lower levels in the liver had higher CCR4–NOT–RNA immunoprecipitation (RIP) enrichment values (Fig 4E). These findings suggest that the CCR4–NOT complex binds to more mRNA species that are expressed at low levels in the liver, such as transcription factors (TFs), cell cycle, and DNA damage-mRNAs, than to mRNA species that are expressed at high levels in the same tissue, such as liver function–related mRNAs

Summary

Introduction

The liver is essential to control energy intake and expenditure so as to maintain organismal energy homeostasis. MRNAs encoding metabolic enzymes are regulated by transcription factors (TFs) such as hepatocyte nuclear factors, peroxisome proliferator–activated receptor α, and sterol regulatory element– binding transcription factor 1 (Horton et al, 2002; Desvergne et al, 2006; Martinez-Jimenes et al, 2010). It is widely accepted that transcription contributes to gene expression control, the importance of posttranscriptional mechanisms, including mRNA decay, for appropriate gene expression is increasingly appreciated (Garneau et al, 2007; Schoenberg et al, 2012). MiR-122, the most abundant microRNA in the liver, suppresses tumor-progressive genes to prevent hepatocarcinogenesis (Hsu et al, 2012; Tsai et al, 2012). Both transcriptional and posttranscriptional mechanisms participate in liver homeostasis

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Conclusion