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Deficiency of WTAP in islet beta cells results in beta cell failure and diabetes in mice

Diabetologia (2023)Cite this article

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Abstract

Aims/hypothesis

N6-methyladenosine (m6A) mRNA methylation and m6A-related proteins (methyltransferase-like 3 [METTL3], methyltransferase-like 14 [METTL14] and YTH domain containing 1 [YTHDC1]) have been shown to regulate islet beta cell function and the pathogenesis of diabetes. However, whether Wilms’ tumour 1-associating protein (WTAP), a key regulator of the m6A RNA methyltransferase complex, regulates islet beta cell failure during pathogenesis of diabetes is largely unknown. The present study aimed to investigate the role of WTAP in the regulation of islet beta cell failure and diabetes.

Methods

Islet beta cell-specific Wtap-knockout and beta cell-specific Mettl3-overexpressing mice were generated for this study. Blood glucose, glucose tolerance, serum insulin, glucose-stimulated insulin secretion (both in vivo and in vitro), insulin levels, glucagon levels and beta cell apoptosis were examined. RNA-seq and MeRIP-seq were performed, and the data were well analysed.

Results

WTAP was downregulated in islet beta cells in type 2 diabetes, due to lipotoxicity and chronic inflammation, and islet beta cell-specific deletion of Wtap (Wtap-betaKO) induced beta cell failure and diabetes. Wtap-betaKO mice showed severe hyperglycaemia (above 20 mmol/l [360 mg/dl]) from 8 weeks of age onwards. Mechanistically, WTAP deficiency decreased m6A mRNA modification and reduced the expression of islet beta cell-specific transcription factors and insulin secretion-related genes by reducing METTL3 protein levels. Islet beta cell-specific overexpression of Mettl3 partially reversed the abnormalities observed in Wtap-betaKO mice.

Conclusions/interpretation

WTAP plays a key role in maintaining beta cell function by regulating m6A mRNA modification depending on METTL3, and the downregulation of WTAP leads to beta cell failure and diabetes.

Data availability

The RNA-seq and MeRIP-seq datasets generated during the current study are available in the Gene Expression Omnibus database repository (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215156; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215360).

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Data availability

The RNA-seq and MeRIP-seq datasets generated during the current study are available in the Gene Expression Omnibus database repository (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215156; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215360).

Abbreviations

BAT:

Brown adipose tissue

iBAT:

Interscapular brown adipose tissue

ER:

Endoplasmic reticulum

GO:

Gene Ontology

GSIS:

Glucose-stimulated insulin secretion

KEGG:

Kyoto Encyclopedia of Genes and Genomes

m6A:

N6-methyladenosine

MeRIP-seq:

Methylated RNA immunoprecipitation sequencing

METTL3:

Methyltransferase-like 3

METTL14:

Methyltransferase-like 14

Mettl3-betaKO:

Beta cell-specific Mettl3-knockout

Mettl3-betaOE:

Beta cell-specific Mettl3-overexpressing

NASH:

Non-alcoholic steatohepatitis

NIK:

NF-κB-inducing kinase

PA:

Palmitic acid

qRT-PCR:

Quantitative reverse transcription PCR

RPKM:

Reads per kilobase per million mapped reads

WTAP:

Wilms’ tumour 1-associating protein

Wtap-betaKO:

Beta cell-specific Wtap-knockout

YTHDC1:

YTH domain containing 1

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Acknowledgements

We thank M. Liu (Tianjin Medical University General Hospital, China) for providing RIP-Cre mice. We also thank Y. Han (Novogene Co., China) for assistance in RNA-seq and MeRIP-seq experiments.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

XL and YY performed the experiments, collected data, analysed and interpreted data, and drafted the manuscript. ZL, YW and JQ analysed and interpreted data, and revised the manuscript. ZC designed the project and wrote the manuscript. ZC is the guarantor of this work. All authors approved the final version to be published.

Funding

This study was supported by the National Natural Science Foundation of China Grant (92057110 and 31971083 to ZC).

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Author notes

  1. Xinzhi Li and Ying Yang contributed equally to this work.

Authors and Affiliations

  1. HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China

    Xinzhi Li, Ying Yang, Zhenzhi Li, Yuqin Wang & Zheng Chen

  2. Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China

    Jingting Qiao

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  1. Xinzhi Li
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Correspondence to Zheng Chen.

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Cite this article

Li, X., Yang, Y., Li, Z. et al. Deficiency of WTAP in islet beta cells results in beta cell failure and diabetes in mice. Diabetologia (2023). https://doi.org/10.1007/s00125-023-05900-z

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Keywords

  • Hyperglycaemia
  • Insulin secretion
  • Islet beta cells
  • METTL3
  • N 6-methyladenosine
  • WTAP