Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells.

The Journal of Biological Chemistry
Kelsie FauldsChristopher J Phiel

Abstract

Glycogen synthase kinase-3 (GSK-3) activity regulates multiple signal transduction pathways and is also a key component of the network responsible for maintaining stem cell pluripotency. Genetic deletion of Gsk-3α and Gsk-3β or inhibition of GSK-3 activity via small molecules promotes stem cell pluripotency, yet the mechanism underlying the role for GSK-3 in this process remains ambiguous. Another cellular process that has been shown to affect stem cell pluripotency is mRNA methylation (m6A). Here, we describe an intersection between these components, the regulation of m6A by GSK-3. We find that protein levels for the RNA demethylase, FTO (fat mass and obesity-associated protein), are elevated in Gsk-3α;Gsk-3β-deficient mouse embryonic stem cells (ESCs). FTO is normally phosphorylated by GSK-3, and MS identified the sites on FTO that are phosphorylated in a GSK-3-dependent fashion. GSK-3 phosphorylation of FTO leads to polyubiquitination, but in Gsk-3 knockout ESCs, that process is impaired, resulting in elevated levels of FTO protein. As a consequence of altered FTO protein levels, mRNAs in Gsk-3 knockout ESCs have 50% less m6A than WT ESCs, and m6A-Seq analysis reveals the specific mRNAs that have reduced m6A modifications. T...Continue Reading

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Citations

Aug 18, 2018·Wiley Interdisciplinary Reviews. RNA·Xiaolei Liu, Peter S Klein
May 28, 2019·Stem Cell Reviews and Reports·Varun Haran, Nibedita Lenka
Aug 23, 2019·Stroke; a Journal of Cerebral Circulation·Anil K ChokkallaRaghu Vemuganti
Aug 26, 2020·Molecular Biotechnology·R Karthiya, Piyush Khandelia
Sep 19, 2020·Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy·Hong LiuHong-Yun Lu
Feb 4, 2021·Journal of Cellular and Molecular Medicine·Zeyan ZhangShanchao Wang
May 1, 2021·International Journal of Molecular Sciences·Michał MarcinkowskiJarosław Poznański
May 18, 2021·Genetics and Molecular Biology·Chengshun LiDongxu Wang

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