1. Mettl14-Mediated m6A Modification Facilitates Liver Regeneration by Maintaining Endoplasmic Reticulum Homeostasis
- Author
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Mingyang Shao, Qing Xu, Menglin Chen, Xiaoyue Cao, Chuan Li, Hong Bu, Yuwei Chen, Yuke Shu, Zhenru Wu, Gang Guo, Yuping Gong, Yongjie Zhou, and Yujun Shi
- Subjects
Male ,0301 basic medicine ,Adenosine ,FoxM1, forkhead box M1 ,IRE1α, inositol requiring enzyme 1 alpha ,XBP1, X-box-binding protein 1 ,STAT, signal transducers and activators of transcription ,RNA Stability ,Mettl3, methyltransferase-like 3 ,Alkbh5, ALKB family member 5 protein ,Apoptosis ,RC799-869 ,AST, aspartate aminotransferase ,WTAP, Wilms’ tumor 1-associated protein ,Endoplasmic Reticulum ,UPR, unfolded protein response ,0302 clinical medicine ,ERK, extracellular signal-regulated kinase ,Homeostasis ,TUDCA, tauroursodeoxycholate ,BrdU, 5-bromo-2-deoxyuridine ,eIF2α, eukaryotic translation initiator factor 2α ,Original Research ,Mice, Knockout ,N6-methyladenosine ,Chemistry ,Gastroenterology ,PI3K, phosphatidylinositol 3-kinase ,Methylation ,Diseases of the digestive system. Gastroenterology ,Cell cycle ,Endoplasmic Reticulum Stress ,Liver regeneration ,Cell biology ,UTR, untranslated region ,medicine.anatomical_structure ,Liver ,PHx, partial hepatectomy ,Organ Specificity ,Hepatocyte ,qPCR, quantitative polymerase chain reaction ,030211 gastroenterology & hepatology ,FTO, fat mass and obesity-associated protein ,ATF6, activating transcription factor 6 ,AMPK, adenosine 5′-monophosphate-activated protein kinase ,JAK, janus kinase ,ER, endoplasmic reticulum ,Taurochenodeoxycholic Acid ,PAS, periodic acid–Schiff ,Necrosis ,03 medical and health sciences ,ALT, alanine aminotransferase ,TM, tunicamycin ,medicine ,Act D, actinomycin ,Animals ,Hepatectomy ,RNA, Messenger ,Cell Proliferation ,Messenger RNA ,Hepatology ,Endoplasmic reticulum ,CDS, coding sequence ,Mettl14 ,Methyltransferases ,FC, fold change ,m6A, N6-methyladenosine ,WT, wild-type ,Liver Regeneration ,m6A-seq, m6A sequencing ,030104 developmental biology ,MRNA Sequencing ,Hepatocytes ,Unfolded protein response ,EIF3A, eukaryotic translation initiation factor 3 subunit A ,HCC, hepatocellular carcinoma ,Peptides ,Transcriptome ,PERK, protein kinase R-like endoplasmic reticulum kinase ,Chop, C/EBP-homologous protein ,MAPK, mitogen-activated protein kinase ,Gene Deletion - Abstract
Background & Aims N6-methyladenosine (m6A), the most prevalent and dynamic posttranscriptional methylation modification of mammalian mRNA, is involved in various biological processes, but its role in liver regeneration has not been characterized. Methods We first conducted transcriptome-wide m6A mRNA sequencing and characterized the expression pattern of m6A in regenerating mouse liver. Next, we generated hepatocyte-specific Mettl3- or Mettl14-deficient mice and investigated their role in liver regeneration. A series of biochemical experiments in vitro and in vivo was further performed to investigate potential mechanisms. Results We identified an overwhelming proportion of m6A-modified genes with initially up-regulated and subsequently down-regulated m6A levels as liver regeneration progressed. Loss of Mettl14 but not of Mettl3 resulted in markedly disrupted liver regeneration, and Mettl14-ablated hepatocytes were arrested in the G1 phase of the cell cycle. Most strikingly, the Mettl14-ablated regenerating liver exhibited extensive parenchymal necrosis. mRNA transcripts, such as Hsp90b1, Erp29, Stt3a, P4hb, and Lman1, encoding proteins involved in polypeptide processing and the endoplasmic reticulum (ER) stress response, were m6A-hypomethylated, and their mRNA and protein levels were subsequently decreased, resulting in unresolved ER stress, hepatocyte death, and inhibited proliferation. Conclusions We demonstrate the essential role of Mettl14 in facilitating liver regeneration by modulating polypeptide-processing proteins in the ER in an m6A-dependent manner., Graphical abstract
- Published
- 2021
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