PMID- 36443649
OWN - NLM
STAT- MEDLINE
DCOM- 20221210
LR  - 20221229
IS  - 1744-8069 (Electronic)
IS  - 1744-8069 (Linking)
VI  - 18
DP  - 2022 Apr
TI  - Methyltransferase-like 3 modulates visceral hypersensitivity through regulating 
      the nuclear export of circKcnk9 in YTHDC1-dependent manner.
PG  - 17448069221144540
LID - 10.1177/17448069221144540 [doi]
LID - 17448069221144540
AB  - Background: Accumulating evidence shows that N6-methyladenosine (m(6)A) 
      modulators contribute to the process of chronic pain. However, the exact 
      mechanisms of m(6)A writers involved in visceral hypersensitivity of Irritable 
      bowel syndrome (IBS) remain unclear. This article aimed to reveal a new mechanism 
      for the progression of IBS. Methods: The IBS-like model was established by 
      neonatal colorectal distention (CRD). The relationship between m(6)A and 
      circKcnk9 was analyzed by bioinformatics, immunofluorescence and RNA fluorescence 
      in situ hybridization (FISH) assays. Visceral hypersensitivity was assessed based 
      on the electromyography (EMG) response of the abdominal external oblique muscle 
      to CRD. In vivo and in vitro studies (including EMG stereotactic infusion, 
      Western blot and qRT-PCR) were utilized to explore the biological functions of 
      related indicators. The bioinformatics, RIP experiments and RNA pull-down assays 
      were used to explore the potential molecular mechanisms. Results: We identified 
      that neonatal CRD increased the level of the m(6)A via methyltransferase-like 3 
      (METTL3) in the hippocampal neurons. Subsequently, knockdown of METTL3 could 
      alleviate visceral hypersensitivity in IBS-like rats. By contrast, overexpression 
      of METTL3 could induce visceral hypersensitivity and activate hippocampal neurons 
      in control rats. Moreover, YTHDC1, the only m(6)A-associated protein predicted by 
      bioinformatics to bind to circKcnk9, modulated visceral hypersensitivity through 
      regulating the nuclear export of circKcnk9 in an m(6)A-dependent manner. Notably, 
      FISH data suggested that the increased nuclear staining of circKcnk9 caused by 
      siYTHDC1 could be recovered by overexpression of YTHDC1 wild type (WT) but not 
      YTHDC1 negative control (NC) in PC12 cells. Conclusions: Our findings reveal a 
      new regulatory mechanism in progress of IBS, that is, METTL3 modulates visceral 
      hypersensitivity through regulating the nuclear export of circKcnk9 in 
      YTHDC1-dependent manner.
FAU - Lin, Wei
AU  - Lin W
AUID- ORCID: 0000-0002-0832-7548
AD  - Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and 
      Neurodegenerative Diseases, School of Basic Medical Sciences, 74551Fujian Medical 
      University, Fuzhou, China.
FAU - Liu, Yuan
AU  - Liu Y
AD  - Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and 
      Neurodegenerative Diseases, School of Basic Medical Sciences, 74551Fujian Medical 
      University, Fuzhou, China.
AD  - Cancer Research Center Nantong, the Affiliated Tumor Hospital of Nantong 
      University, Nantong, China.
FAU - Zhou, Yifei
AU  - Zhou Y
AD  - Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and 
      Neurodegenerative Diseases, School of Basic Medical Sciences, 74551Fujian Medical 
      University, Fuzhou, China.
FAU - Lin, Mengying
AU  - Lin M
AD  - Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and 
      Neurodegenerative Diseases, School of Basic Medical Sciences, 74551Fujian Medical 
      University, Fuzhou, China.
FAU - Liu, Congxu
AU  - Liu C
AD  - Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and 
      Neurodegenerative Diseases, School of Basic Medical Sciences, 74551Fujian Medical 
      University, Fuzhou, China.
FAU - Tang, Ying
AU  - Tang Y
AD  - Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and 
      Neurodegenerative Diseases, School of Basic Medical Sciences, 74551Fujian Medical 
      University, Fuzhou, China.
FAU - Wu, Bin
AU  - Wu B
AD  - Department of Pediatrics, the First Affiliated Hospital, Fujian Medical 
      University, Fuzhou, China.
FAU - Lin, Chun
AU  - Lin C
AD  - Pain Research Institute, Fujian Provincial Key Laboratory of Brain Aging and 
      Neurodegenerative Diseases, School of Basic Medical Sciences, 74551Fujian Medical 
      University, Fuzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pain
JT  - Molecular pain
JID - 101242662
RN  - EC 2.1.1.- (Methyltransferases)
RN  - 63231-63-0 (RNA)
RN  - 0 (Ythdc1 protein, rat)
RN  - EC 2.1.1.62 (Mettl3 protein, rat)
SB  - IM
MH  - Animals
MH  - Rats
MH  - Active Transport, Cell Nucleus
MH  - *Hypersensitivity
MH  - In Situ Hybridization, Fluorescence
MH  - *Irritable Bowel Syndrome
MH  - Methyltransferases/genetics
MH  - RNA
MH  - *Visceral Pain
PMC - PMC9730012
OTO - NOTNLM
OT  - Irritable bowel syndrome
OT  - YTHDC1
OT  - hippocampus
OT  - methyltransferase-like 3
OT  - visceral hypersensitivity
COIS- The author(s) declared no potential conflicts of interest with respect to the 
      research, authorship, and/or publication of this article.
EDAT- 2022/11/29 06:00
MHDA- 2022/12/10 06:00
PMCR- 2022/12/05
CRDT- 2022/11/28 23:52
PHST- 2022/11/29 06:00 [pubmed]
PHST- 2022/12/10 06:00 [medline]
PHST- 2022/11/28 23:52 [entrez]
PHST- 2022/12/05 00:00 [pmc-release]
AID - 10.1177_17448069221144540 [pii]
AID - 10.1177/17448069221144540 [doi]
PST - ppublish
SO  - Mol Pain. 2022 Apr;18:17448069221144540. doi: 10.1177/17448069221144540.