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Series GSE185109 Query DataSets for GSE185109
Status Public on Sep 30, 2021
Title HRD1-mediated METTL14 degradation regulates m6A mRNA modification to suppress ER proteotoxic liver disease
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Summary Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers unfolded protein response (UPR) for stress adaptation, the failure of which induces cell apoptosis and tissue/organ damage. The molecular switches underlying how the UPR selects for stress adaptation over apoptosis remain unknown. Here we discovered that accumulation of unfolded/misfolded proteins selectively induces N6-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes CHOP mRNA decay through its 3’UTR N6-adenosine methylation (m6A) to inhibit its downstream pro-apoptotic target genes expression. UPR induces METTL14 expression through competing the HRD1-ERAD machinery to block METTL14 ubiquitination and degradation. Therefore, mice with liver-specific METTL14 deletion are highly susceptible to both acute pharmacological and alpha-1 antitrypsin (AAT) deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protects METTL14 knockout mice from ER stress-induced liver damage. Our study reveals a crosstalk between ER stress and mRNA m6A pathways, the ERm6A pathway, for ER stress adaptation to proteotoxicity.
 
Overall design To investigate the molecular mechanisms underlying how METTL14 protects mice from UPR-induced liver damage, we analyzed the mRNA expression profile in liver from Tm treated METTL14 LKO and WT mice by transcriptome-wide mRNA sequencing.
 
Contributor(s) Wei J, Harada BT, He C, Fang D
Citation(s) 34847358
Submission date Sep 30, 2021
Last update date Dec 01, 2021
Contact name Bryan T Harada
E-mail(s) btharada@uchicago.edu
Organization name University of Chicago
Department Chemistry
Street address 929 E 57th St
City Chicago
State/province IL
ZIP/Postal code 60637
Country USA
 
Platforms (1)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (8)
GSM5606639 Wild-type rep1 input
GSM5606640 Wild-type rep2 input
GSM5606641 Knockout rep1 input
Relations
BioProject PRJNA767663
SRA SRP339507

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE185109_differentialExpression.txt.gz 851.4 Kb (ftp)(http) TXT
GSE185109_peak_ko.txt.gz 449.9 Kb (ftp)(http) TXT
GSE185109_peak_wt.txt.gz 200.3 Kb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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