Formichetti Sara, Sadowska Agnieszka, Ascolani Michela, Hansen Julia, Ganter Kerstin, Lancrin Christophe, Humphreys Neil, Boulard Mathieu
Epigenetics & Neurobiology Unit, EMBL Rome, European Molecular Biology Laboratory, Italy.
Collaboration for joint PhD degree between EMBL and Heidelberg University, Germany.
PLoS Genet. 2025 Jan 9;21(1):e1011507. doi: 10.1371/journal.pgen.1011507. eCollection 2025 Jan.
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.
核蛋白和胞质蛋白的可逆糖基化（O-连接的N-乙酰葡糖胺化）由单一酶即O-连接的N-乙酰葡糖胺转移酶（OGT）催化。哺乳动物的Ogt基因位于X染色体上，对胚胎发育和增殖细胞的存活至关重要。我们通过创建一系列四个单氨基酸取代的小鼠等位基因来扰乱OGT在体内的功能，将OGT的催化活性降低到不同程度。胚胎致死的严重程度与OGT催化受损的程度成正比，表明O-连接的N-乙酰葡糖胺修饰本身是早期发育所必需的。我们鉴定出了干扰O-连接的N-乙酰葡糖胺稳态但与胚胎发生相容的低表达Ogt等位基因。对不同发育阶段突变胚胎转录组的分析表明，O-连接的N-乙酰葡糖胺减少导致了性别二态性发育延迟。此外，OGT酶活性的轻度降低足以在体内放松对内源逆转录病毒的沉默。
