PMID- 33992834
OWN - NLM
STAT- MEDLINE
DCOM- 20220322
LR  - 20220322
IS  - 2352-345X (Electronic)
IS  - 2352-345X (Linking)
VI  - 12
IP  - 3
DP  - 2021
TI  - METTL3/METTL14 Transactivation and m(6)A-Dependent TGF-beta1 Translation in 
      Activated Kupffer Cells.
PG  - 839-856
LID - S2352-345X(21)00096-5 [pii]
LID - 10.1016/j.jcmgh.2021.05.007 [doi]
AB  - BACKGROUND AND AIMS: Transforming growth factor beta1 (TGF-beta1) secreted from 
      activated Kupffer cells (KC) promotes the progression of nonalcoholic 
      steatohepatitis (NASH) to liver fibrosis. N6-methyladenosine (m(6)A) RNA 
      modification participates in various cell stress responses, yet it remains 
      unknown whether it plays a role in TGF-beta1 upregulation in activated KCs. METHODS: 
      Western blot, dot blot, and liquid chromatography with tandem mass spectrometry 
      were used to determine the expression of m(6)A methyltransferase, METTL3, and 
      METTL14, as well as global m(6)A modification. RNA-sequencing and m(6)A-seq were 
      employed to screen differentially expressed genes and responsive m(6)A peaks. 
      Nuclear factor kappaB (NF-kappaB)-mediated METTL3/METTL14 transactivation were validated 
      with chromatin immunoprecipitation polymerase chain reaction and dual-luciferase 
      reporter system, and the role of m(6)A in TGF-beta1 upregulation was further 
      verified in METTL3/METTL14-deficient KCs and myeloid lineage cell-specific 
      METTL14 knockout mice. RESULTS: Serum lipopolysaccharide (LPS) concentration is 
      increased in high-fat diet-induced NASH rats. TGF-beta1 upregulation is closely 
      associated with METTL3/METTL14 upregulation and global m(6)A hypermethylation, in 
      both NASH rat liver and LPS-activated KCs. LPS-responsive m(6)A peaks are 
      identified on the 5' untranslated region (UTR) of TGF-beta1 messenger RNA (mRNA). 
      NF-kappaB directly transactivates METTL3 and METTL14 genes. LPS-stimulated TGF-beta1 
      expression is abolished in METTL3/METTL14-deficient KCs and myeloid lineage 
      cell-specific METTL14 knockout mice. Mutation of m(6)A sites on the 5'UTR of 
      TGF-beta1 mRNA blocks LPS-induced increase of luciferase reporter activity. 
      CONCLUSIONS: NF-kappaB acts as transcription factor to transactivate METTL3/METTL14 
      genes upon LPS challenge, leading to global RNA m(6)A hypermethylation. Increased 
      m(6)A on the 5'UTR of TGF-beta1 mRNA results in m(6)A-dependent translation of 
      TGF-beta1 mRNA in a cap-independent manner. We identify a novel role of m(6)A 
      modification in TGF-beta1 upregulation, which helps to shed light on the molecular 
      mechanism of NASH progression.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Feng, Yue
AU  - Feng Y
AD  - MOE Joint International Research Laboratory of Animal Health & Food Safety, 
      Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China; Key Laboratory of 
      Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing 
      Agricultural University, Nanjing, Jiangsu, P. R. China.
FAU - Dong, Haibo
AU  - Dong H
AD  - MOE Joint International Research Laboratory of Animal Health & Food Safety, 
      Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China; Key Laboratory of 
      Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing 
      Agricultural University, Nanjing, Jiangsu, P. R. China.
FAU - Sun, Bo
AU  - Sun B
AD  - MOE Joint International Research Laboratory of Animal Health & Food Safety, 
      Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China; Key Laboratory of 
      Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing 
      Agricultural University, Nanjing, Jiangsu, P. R. China.
FAU - Hu, Yun
AU  - Hu Y
AD  - MOE Joint International Research Laboratory of Animal Health & Food Safety, 
      Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China; Key Laboratory of 
      Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing 
      Agricultural University, Nanjing, Jiangsu, P. R. China.
FAU - Yang, Yang
AU  - Yang Y
AD  - MOE Joint International Research Laboratory of Animal Health & Food Safety, 
      Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China; Key Laboratory of 
      Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing 
      Agricultural University, Nanjing, Jiangsu, P. R. China.
FAU - Jia, Yimin
AU  - Jia Y
AD  - MOE Joint International Research Laboratory of Animal Health & Food Safety, 
      Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China; Key Laboratory of 
      Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing 
      Agricultural University, Nanjing, Jiangsu, P. R. China.
FAU - Jia, Longfei
AU  - Jia L
AD  - Division of Nutritional Sciences, Cornell University, Ithaca, New York.
FAU - Zhong, Xiang
AU  - Zhong X
AD  - College of Animal Science and Technology, Nanjing Agricultural University, 
      Nanjing, Jiangsu, P. R. China.
FAU - Zhao, Ruqian
AU  - Zhao R
AD  - MOE Joint International Research Laboratory of Animal Health & Food Safety, 
      Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China; Key Laboratory of 
      Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing 
      Agricultural University, Nanjing, Jiangsu, P. R. China. Electronic address: 
      zhaoruqian@njau.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210513
PL  - United States
TA  - Cell Mol Gastroenterol Hepatol
JT  - Cellular and molecular gastroenterology and hepatology
JID - 101648302
RN  - 0 (5' Untranslated Regions)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Transforming Growth Factor beta1)
RN  - CLE6G00625 (N-methyladenosine)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - K72T3FS567 (Adenosine)
SB  - IM
CIN - Cell Mol Gastroenterol Hepatol. 2021;12(3):1147-1148. PMID: 34224680
MH  - 5' Untranslated Regions
MH  - Adenosine/*analogs & derivatives/metabolism
MH  - Animals
MH  - Base Sequence
MH  - Diet, High-Fat
MH  - Disease Models, Animal
MH  - Gene Expression Regulation
MH  - Gene Knockdown Techniques
MH  - Kupffer Cells/*metabolism
MH  - Liver Cirrhosis/etiology/metabolism/pathology
MH  - Methylation
MH  - Methyltransferases/deficiency/*metabolism
MH  - Models, Biological
MH  - *Protein Biosynthesis
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats
MH  - Transcription Factor RelA/metabolism
MH  - *Transcriptional Activation
MH  - Transforming Growth Factor beta1/*genetics/metabolism
PMC - PMC8340128
OTO - NOTNLM
OT  - N6-Methyladenosine
OT  - NASH
OT  - NF-kappaB
OT  - TGF-beta1
EDAT- 2021/05/17 06:00
MHDA- 2022/03/23 06:00
PMCR- 2021/05/13
CRDT- 2021/05/16 20:40
PHST- 2021/01/19 00:00 [received]
PHST- 2021/05/07 00:00 [revised]
PHST- 2021/05/07 00:00 [accepted]
PHST- 2021/05/17 06:00 [pubmed]
PHST- 2022/03/23 06:00 [medline]
PHST- 2021/05/16 20:40 [entrez]
PHST- 2021/05/13 00:00 [pmc-release]
AID - S2352-345X(21)00096-5 [pii]
AID - 10.1016/j.jcmgh.2021.05.007 [doi]
PST - ppublish
SO  - Cell Mol Gastroenterol Hepatol. 2021;12(3):839-856. doi: 
      10.1016/j.jcmgh.2021.05.007. Epub 2021 May 13.