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Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1-Dio3 locus miRNAs

Liko, Dritan and Rzepiela, Andrzej and Vukojevic, Vanja and Zavolan, Mihaela and Hall, Michael N.. (2020) Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1-Dio3 locus miRNAs. Proceedings of the National Academy of Sciences, 117 (3). pp. 1524-1532.

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Official URL: https://edoc.unibas.ch/74398/

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Abstract

Loss of the tumor suppressor tuberous sclerosis complex 1 (Tsc1) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1-knockout mice, and found that miRNAs of the delta-like homolog 1 (Dlk1)-deiodinase iodothyronine type III (Dio3) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver. Furthermore, we show that miRNA is a downstream effector of hyperactive mTORC1 signaling.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Zavolan)
UniBasel Contributors:Hall, Michael N. and Zavolan, Mihaela and Rzepiela, Andrzej
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
ISSN:0027-8424
e-ISSN:1091-6490
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:22 Feb 2020 04:10
Deposited On:10 Feb 2020 11:54

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