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

Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m 6 A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m 6 A in liver development...

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Published in:Nature communications 2022-08, Vol.13 (1), p.4555-4555, Article 4555
Main Authors: Xu, Yan, Zhou, Zhuowei, Kang, Xinmei, Pan, Lijie, Liu, Chang, Liang, Xiaoqi, Chu, Jiajie, Dong, Shuai, Li, Yanli, Liu, Qiuli, Sun, Yuetong, Yu, Shanshan, Zhang, Qi
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Subjects:
13/1
13/106
13/51
14
14/19
14/34
14/63
38
38/90
38/91
45
631/208/135
631/337/572/2102
64
64/60
692/4020/4021/288/2032
Apoptosis
Gene sequencing
Hepatocyte nuclear factor 4
Hepatocytes
Homeostasis
Humanities and Social Sciences
Lethality
Life span
Liver
multidisciplinary
N6-methyladenosine
Physiology
RNA modification
Science
Science (multidisciplinary)
Steatosis
Transcription factors
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creator Xu, Yan
Zhou, Zhuowei
Kang, Xinmei
Pan, Lijie
Liu, Chang
Liang, Xiaoqi
Chu, Jiajie
Dong, Shuai
Li, Yanli
Liu, Qiuli
Sun, Yuetong
Yu, Shanshan
Zhang, Qi
description Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m 6 A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m 6 A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m 6 A 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. m 6 A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m 6 A, including Hnf4a , a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m 6 A 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-Cre ERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m 6 A modification in liver development. m 6 A is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. Here the authors show a role for Mettl3-mediated RNA m 6 A modification in postnatal liver development by regulating the Hnf4a-centered transcriptional network
doi_str_mv 10.1038/s41467-022-32169-4
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N6-methyladenosine (m 6 A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m 6 A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m 6 A 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. m 6 A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m 6 A, including Hnf4a , a master regulator for hepatic parenchymal formation. Deleting Mettl3 reduces m 6 A 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-Cre ERT2 does not affect liver homeostasis. Our study identifies a dynamic role of Mettl3-mediated RNA m 6 A modification in liver development. m 6 A is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. 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N6-methyladenosine (m 6 A) is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. However, the function of m 6 A in liver development remains elusive. Here we dissect the role of Mettl3-mediated m 6 A 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. m 6 A-RIP sequencing and RNA-sequencing reveal that mRNAs of a series of crucial liver-enriched transcription factors are modified by m 6 A, including Hnf4a , a master regulator for hepatic parenchymal formation. 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subjects 13/1
13/106
13/51
14
14/19
14/34
14/63
38
38/90
38/91
45
631/208/135
631/337/572/2102
64
64/60
692/4020/4021/288/2032
Apoptosis
Gene sequencing
Hepatocyte nuclear factor 4
Hepatocytes
Homeostasis
Humanities and Social Sciences
Lethality
Life span
Liver
multidisciplinary
N6-methyladenosine
Physiology
RNA modification
Science
Science (multidisciplinary)
Steatosis
Transcription factors
title Mettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a
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