A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos

• Published in: Genes & development 2024-02, Vol.38 (3-4), p.131-150
• Main Authors: Giaccari, Carlo, Cecere, Francesco, Argenziano, Lucia, Pagano, Angela, Galvao, Antonio, Acampora, Dario, Rossi, Gianna, Hay Mele, Bruno, Acurzio, Basilia, Coonrod, Scott, Cubellis, Maria Vittoria, Cerrato, Flavia, Andrews, Simon, Cecconi, Sandra, Kelsey, Gavin, Riccio, Andrea
• Format: Article
• Language: English
• Subjects: Research Papers
• ISSN: 0890-9369; 1549-5477; 1549-5477
• DOI: 10.1101/gad.351238.123

Maternal inactivation of genes encoding components of the subcortical maternal complex (SCMC) and its associated member, PADI6, generally results in early embryo lethality. In humans, SCMC gene variants were found in the healthy mothers of children affected by multilocus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. We generated a mouse line carrying a missense variant that was identified in a family with Beckwith-Wiedemann syndrome and MLID. If homozygous in female mice, this variant resulted in interruption of embryo development at the two-cell stage. Single-cell multiomic analyses demonstrated defective maturation of mutant oocytes and incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, up-regulation of maternal decay genes, and developmental delay in two-cell embryos developing from mutant oocytes but little effect on genomic imprinting. Western blotting and immunofluorescence analyses showed reduced levels of UHRF1 in oocytes and abnormal localization of DNMT1 and UHRF1 in both oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue the developmental arrest of mutant embryos. Taken together, this study demonstrates that PADI6 controls both nuclear and cytoplasmic oocyte processes that are necessary for preimplantation epigenetic reprogramming and ZGA.