Genetic gradual reduction of OGT activity unveils the essential role of O-GlcNAc in the mouse embryo.

IF 4 2区 生物学 Q1 GENETICS & HEREDITY
PLoS Genetics Pub Date : 2025-01-09 eCollection Date: 2025-01-01 DOI:10.1371/journal.pgen.1011507
Sara Formichetti, Agnieszka Sadowska, Michela Ascolani, Julia Hansen, Kerstin Ganter, Christophe Lancrin, Neil Humphreys, Mathieu Boulard
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引用次数: 0

Abstract

The reversible glycosylation of nuclear and cytoplasmic proteins (O-GlcNAcylation) is catalyzed by a single enzyme, namely O-GlcNAc transferase (OGT). The mammalian Ogt gene is X-linked, and it is essential for embryonic development and for the viability of proliferating cells. We perturbed OGT's function in vivo by creating a murine allelic series of four single amino acid substitutions, reducing OGT's catalytic activity to a range of degrees. The severity of the embryonic lethality was proportional to the extent of impairment of OGT's catalysis, demonstrating that the O-GlcNAc modification itself is required for early development. We identified hypomorphic Ogt alleles that perturb O-GlcNAc homeostasis while being compatible with embryogenesis. The analysis of the transcriptomes of the mutant embryos at different developmental stages suggested a sexually-dimorphic developmental delay caused by the decrease in O-GlcNAc. Furthermore, a mild reduction of OGT's enzymatic activity was sufficient to loosen the silencing of endogenous retroviruses in vivo.

OGT活性的遗传逐渐降低揭示了O-GlcNAc在小鼠胚胎中的重要作用。
核蛋白和细胞质蛋白的可逆糖基化(o - glcnac酰化)是由一种酶催化的,即O-GlcNAc转移酶(OGT)。哺乳动物的Ogt基因是x连锁的,它对胚胎发育和增殖细胞的生存能力至关重要。我们通过创建一个由四个单氨基酸取代的小鼠等位基因序列来干扰OGT在体内的功能,在一定程度上降低了OGT的催化活性。胚胎致死的严重程度与OGT催化功能受损的程度成正比,表明O-GlcNAc修饰本身是早期发育所必需的。我们发现了在与胚胎发生相容的同时干扰O-GlcNAc稳态的半胚性Ogt等位基因。对不同发育阶段突变胚胎的转录组分析表明,O-GlcNAc的减少导致了两性二态发育延迟。此外,OGT酶活性的轻度降低足以解除体内内源性逆转录病毒的沉默。
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来源期刊
PLoS Genetics
PLoS Genetics GENETICS & HEREDITY-
自引率
2.20%
发文量
438
期刊介绍: PLOS Genetics is run by an international Editorial Board, headed by the Editors-in-Chief, Greg Barsh (HudsonAlpha Institute of Biotechnology, and Stanford University School of Medicine) and Greg Copenhaver (The University of North Carolina at Chapel Hill). Articles published in PLOS Genetics are archived in PubMed Central and cited in PubMed.
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