Multi-omics after O-GlcNAc alteration identified cellular processes promoting aneuploidy after loss of O-GlcNAc transferase

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2024-10-29 DOI:10.1016/j.molmet.2024.102060

Samuel S. Boyd , Dakota R. Robarts , Khue Nguyen , Maite Villar , Ibtihal M. Alghusen , Manasi Kotulkar , Aspin Denson , Halyna Fedosyuk , Stephen A. Whelan , Norman C.Y. Lee , John Hanover , Wagner B. Dias , Ee Phie Tan , Steven R. McGreal , Antonio Artigues , Russell H. Swerdlow , Jeffrey A. Thompson , Udayan Apte , Chad Slawson

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引用次数: 0

Abstract

Objective

Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates.

Method

To address the pleotropic nature of O-GlcNAc, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics.

Results

We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions. Moreover, we identified pathways in OGT knockout samples associated with increased aneuploidy. To test and validate these pathways, we induced liver growth in OGT knockouts by partial hepatectomy. OGT knockout livers showed a robust aneuploidy phenotype with disruptions in mitosis, nutrient sensing, protein metabolism/amino acid metabolism, stress response, and HIPPO signaling demonstrating how OGT is essential in controlling aneuploidy pathways.

Conclusion

These data show how a multi-Omics platform can disentangle the pleotropic nature of O-GlcNAc to discern how OGT fine-tunes multiple cellular pathways involved in aneuploidy.

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O-GlcNAc改变后的多重形态学发现了O-GlcNAc转移酶缺失后促进非整倍体的细胞过程。

O-GlcNAcylation是一种细胞内的单糖翻译后修饰，由于O-GlcNAc的多向性及其调控的信号通路广泛，因此很难对其进行药物或遗传操作。为了解决这个问题，我们采用了OGT（O-GlcNAc转移酶）、OGA（O-GlcNAcase）肝脏基因敲除或药理抑制OGA的方法，并结合了多重组学分析和生物信息学。我们发现了许多基因、蛋白质、磷酸蛋白或代谢物在不同条件下发生了反向或等效变化。此外，我们还在 OGT 基因敲除样本中发现了与非整倍体增加相关的通路。为了测试和验证这些通路，我们通过部分肝切除术诱导 OGT 基因敲除者的肝脏生长。OGT基因敲除的肝脏表现出强大的非整倍体表型，有丝分裂、营养传感、蛋白质代谢/氨基酸代谢、应激反应和HIPPO信号转导均出现紊乱，这表明OGT在控制非整倍体途径中至关重要。此外，这些数据还显示了多重分子生物学平台如何能够辨别 OGT 如何微调非整倍体所涉及的多种细胞通路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.