IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-32169-4.html
   My bibliography  Save this article

Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a

Author

Listed:
  • Yan Xu

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Zhuowei Zhou

    (Sun Yat-sen University)

  • Xinmei Kang

    (Sun Yat-sen University)

  • Lijie Pan

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Chang Liu

    (Sun Yat-sen University)

  • Xiaoqi Liang

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Jiajie Chu

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Shuai Dong

    (Sun Yat-sen University)

  • Yanli Li

    (Sun Yat-sen University)

  • Qiuli Liu

    (Sun Yat-sen University)

  • Yuetong Sun

    (Sun Yat-sen University)

  • Shanshan Yu

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Qi Zhang

    (Sun Yat-sen University
    Sun Yat-sen University
    Sun Yat-sen University)

Abstract

Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m6A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m6A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m6A modification in postnatal liver development and homeostasis. Knocking out Mettl3 perinatally with Alb-Cre (Mettl3 cKO) induces apoptosis and steatosis of hepatocytes, results in severe liver injury, and finally leads to postnatal lethality within 7 weeks. m6A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m6A, including Hnf4a, a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m6A modification on Hnf4a, decreases its transcript stability in an Igf2bp1-dependent manner, and down-regulates Hnf4a expression, while overexpressing Hnf4a with AAV8 alleviates the liver injury and prolongs the lifespan of Mettl3 cKO mice. However, knocking out Mettl3 in adults using Alb-CreERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m6A modification in liver development.

Suggested Citation

  • Yan Xu & Zhuowei Zhou & Xinmei Kang & Lijie Pan & Chang Liu & Xiaoqi Liang & Jiajie Chu & Shuai Dong & Yanli Li & Qiuli Liu & Yuetong Sun & Shanshan Yu & Qi Zhang, 2022. "Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32169-4
    DOI: 10.1038/s41467-022-32169-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-32169-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-32169-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jiadong Liu & Mingwei Gao & Jiangping He & Kaixin Wu & Siyuan Lin & Lingmei Jin & Yaping Chen & He Liu & Junjie Shi & Xiwei Wang & Lei Chang & Yingying Lin & Yu-Li Zhao & Xiaofei Zhang & Man Zhang & G, 2021. "The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity," Nature, Nature, vol. 591(7849), pages 322-326, March.
    2. Xiang Wang & Jing Feng & Yuan Xue & Zeyuan Guan & Delin Zhang & Zhu Liu & Zhou Gong & Qiang Wang & Jinbo Huang & Chun Tang & Tingting Zou & Ping Yin, 2016. "Structural basis of N6-adenosine methylation by the METTL3–METTL14 complex," Nature, Nature, vol. 534(7608), pages 575-578, June.
    3. Chunxia Zhang & Yusheng Chen & Baofa Sun & Lu Wang & Ying Yang & Dongyuan Ma & Junhua Lv & Jian Heng & Yanyan Ding & Yuanyuan Xue & Xinyan Lu & Wen Xiao & Yun-Gui Yang & Feng Liu, 2017. "m6A modulates haematopoietic stem and progenitor cell specification," Nature, Nature, vol. 549(7671), pages 273-276, September.
    4. Xiao Wang & Zhike Lu & Adrian Gomez & Gary C. Hon & Yanan Yue & Dali Han & Ye Fu & Marc Parisien & Qing Dai & Guifang Jia & Bing Ren & Tao Pan & Chuan He, 2014. "N6-methyladenosine-dependent regulation of messenger RNA stability," Nature, Nature, vol. 505(7481), pages 117-120, January.
    5. Wenqi Xu & Jiahui Li & Chenxi He & Jing Wen & Honghui Ma & Bowen Rong & Jianbo Diao & Liyong Wang & Jiahua Wang & Feizhen Wu & Li Tan & Yujiang Geno Shi & Yang Shi & Hongjie Shen, 2021. "METTL3 regulates heterochromatin in mouse embryonic stem cells," Nature, Nature, vol. 591(7849), pages 317-321, March.
    6. Hua-Bing Li & Jiyu Tong & Shu Zhu & Pedro J. Batista & Erin E. Duffy & Jun Zhao & Will Bailis & Guangchao Cao & Lina Kroehling & Yuanyuan Chen & Geng Wang & James P. Broughton & Y. Grace Chen & Yuval , 2017. "m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways," Nature, Nature, vol. 548(7667), pages 338-342, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Zhiyuan Luo & Jiacheng Zhang & Jingyi Fei & Shengdong Ke, 2022. "Deep learning modeling m6A deposition reveals the importance of downstream cis-element sequences," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Xiao Han & Lijuan Liu & Saihua Huang & Wenfeng Xiao & Yajing Gao & Weitao Zhou & Caiyan Zhang & Hongmei Zheng & Lan Yang & Xueru Xie & Qiuyan Liang & Zikun Tu & Hongmiao Yu & Jinrong Fu & Libo Wang & , 2023. "RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Belinda Baquero-Pérez & Ivaylo D. Yonchev & Anna Delgado-Tejedor & Rebeca Medina & Mireia Puig-Torrents & Ian Sudbery & Oguzhan Begik & Stuart A. Wilson & Eva Maria Novoa & Juana Díez, 2024. "N6-methyladenosine modification is not a general trait of viral RNA genomes," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Yanan Liu & Longmiao Hu & Zhengzhen Wu & Kun Yuan & Guangliang Hong & Zhengke Lian & Juanjuan Feng & Na Li & Dali Li & Jiemin Wong & Jiekai Chen & Mingyao Liu & Jiangping He & Xiufeng Pang, 2023. "Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Chang Liu & Xiaoyang Dou & Yutao Zhao & Linda Zhang & Lisheng Zhang & Qing Dai & Jun Liu & Tong Wu & Yu Xiao & Chuan He, 2024. "IGF2BP3 promotes mRNA degradation through internal m7G modification," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Xin Yang & Robinson Triboulet & Qi Liu & Erdem Sendinc & Richard I. Gregory, 2022. "Exon junction complex shapes the m6A epitranscriptome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Yongli Shan & Yanqi Zhang & Yanxing Wei & Cong Zhang & Huaisong Lin & Jiangping He & Junwei Wang & Wenjing Guo & Heying Li & Qianyu Chen & Tiancheng Zhou & Qi Xing & Yancai Liu & Jiekai Chen & Guangji, 2024. "METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    8. Huaxia Shi & Ying Xu & Na Tian & Ming Yang & Fu-Sen Liang, 2022. "Inducible and reversible RNA N6-methyladenosine editing," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    9. Haiyan Zhang & Xiaojing Luo & Wei Yang & Zhiying Wu & Zhicong Zhao & Xin Pei & Xue Zhang & Chonghao Chen & Josh Haipeng Lei & Qingxia Shi & Qi Zhao & Yanxing Chen & Wenwei Wu & Zhaolei Zeng & Huai-Qia, 2024. "YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    10. Chunhong Yu & Xiaoyun Lei & Fang Chen & Song Mao & Lu Lv & Honglu Liu & Xueying Hu & Runhan Wang & Licong Shen & Na Zhang & Yang Meng & Yunfan Shen & Jiale Chen & Pishun Li & Shi Huang & Changwei Lin , 2022. "ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    11. Zhen-Dong Zhong & Ying-Yuan Xie & Hong-Xuan Chen & Ye-Lin Lan & Xue-Hong Liu & Jing-Yun Ji & Fu Wu & Lingmei Jin & Jiekai Chen & Daniel W. Mak & Zhang Zhang & Guan-Zheng Luo, 2023. "Systematic comparison of tools used for m6A mapping from nanopore direct RNA sequencing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    12. Shujie Chen, & Lu Zhang & Mengjie Li & Ying Zhang & Meng Sun & Lingfang Wang & Jiebo Lin & Yun Cui & Qian Chen & Chenqi Jin & Xiang Li & Boya Wang & Hao Chen & Tianhua Zhou & Liangjing Wang & Chih-Hun, 2022. "Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    13. Sakshi Jain & Lukasz Koziej & Panagiotis Poulis & Igor Kaczmarczyk & Monika Gaik & Michal Rawski & Namit Ranjan & Sebastian Glatt & Marina V. Rodnina, 2023. "Modulation of translational decoding by m6A modification of mRNA," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    14. Bin Li & Wen Xi & Ying Bai & Xue Liu & Yuan Zhang & Lu Li & Liang Bian & Chenchen Liu & Ying Tang & Ling Shen & Li Yang & Xiaochun Gu & Jian Xie & Zhongqiu Zhou & Yu Wang & Xiaoyu Yu & Jianhong Wang &, 2023. "FTO-dependent m6A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    15. Hyun Jung Hwang & Hongseok Ha & Ban Seok Lee & Bong Heon Kim & Hyun Kyu Song & Yoon Ki Kim, 2022. "LC3B is an RNA-binding protein to trigger rapid mRNA degradation during autophagy," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    16. Christopher P. Watkins & Wen Zhang & Adam C. Wylder & Christopher D. Katanski & Tao Pan, 2022. "A multiplex platform for small RNA sequencing elucidates multifaceted tRNA stress response and translational regulation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Guoqiang Zhang & Yongru Xu & Xiaona Wang & Yuanxiang Zhu & Liangliang Wang & Wenxin Zhang & Yiru Wang & Yajie Gao & Xuna Wu & Ying Cheng & Qinmiao Sun & Dahua Chen, 2022. "Dynamic FMR1 granule phase switch instructed by m6A modification contributes to maternal RNA decay," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Xiaojie Ma & Jie Cao & Ziyu Zhou & Yunkun Lu & Qin Li & Yan Jin & Guo Chen & Weiyun Wang & Wenyan Ge & Xi Chen & Zhensheng Hu & Xiao Shu & Qian Deng & Jiaqi Pu & Chengzhen Liang & Junfen Fu & Jianzhao, 2022. "N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    19. Man Zhang & Yunping Zeng & Rong Peng & Jie Dong & Yelin Lan & Sujuan Duan & Zhenyi Chang & Jian Ren & Guanzheng Luo & Bing Liu & Kamil Růžička & Kewei Zhao & Hong-Bin Wang & Hong-Lei Jin, 2022. "N6-methyladenosine RNA modification regulates photosynthesis during photodamage in plants," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    20. Xiangbin Ruan & Kaining Hu & Xiaochang Zhang, 2023. "PIE-seq: identifying RNA-binding protein targets by dual RNA-deaminase editing and sequencing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32169-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.