TY - JOUR
T1 - The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation
AU - Takahashi, Akinori
AU - Suzuki, Toru
AU - Soeda, Shou
AU - Takaoka, Shohei
AU - Kobori, Shungo
AU - Yamaguchi, Tomokazu
AU - Aly Mohamed, Haytham Mohamed
AU - Yanagiya, Akiko
AU - Abe, Takaya
AU - Shigeta, Mayo
AU - Furuta, Yasuhide
AU - Kuba, Keiji
AU - Yamamoto, Tadashi
N1 - Funding Information:
We thank Dr Pierre Chambon and Dr Daniel Metzger (GIE-CERBM) for providing Alb-CreERT2 mice. We thank Okinawa Institute of Science and Technology Graduate University (OIST) for generous support to the Cell Signal Unit. We also thank the OIST DNA Sequencing Section for preparing Illumina sequence libraries and for performing HiSeq sequencing. This work was supported by a Grant-in-Aid for Scientific Research (S) (21229006), Scientific Research (C) (17K07292, 18K06975, 18K07079), Japan Society for the Promotion of Science Fellows (10J08349), Young Scientists (B) (25860761), and Scientific Research on Innovative Areas in a proposed research area (25121734, 17H06018) from the Japan Ministry of Education, Culture, Sports, Science and Technology. This work was also supported by a Grant from Joint Research Project of the Institute of Medical Science, the University of Tokyo.
Publisher Copyright:
© 2020 Takahashi et al.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
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U2 - 10.26508/lsa.201900494
DO - 10.26508/lsa.201900494
M3 - Article
C2 - 32238456
AN - SCOPUS:85082979443
SN - 2575-1077
VL - 3
JO - Life Science Alliance
JF - Life Science Alliance
IS - 5
M1 - e201900494
ER -
