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.

Autor:	Giaccari C; Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli,' Caserta 81100, Italy., Cecere F; Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli,' Caserta 81100, Italy., Argenziano L; Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli,' Caserta 81100, Italy., Pagano A; Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli,' Caserta 81100, Italy., Galvao A; Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom.; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.; Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Olsztyn 10-748, Poland., Acampora D; Institute of Genetics and Biophysics (IGB) 'Adriano Buzzati-Traverso,' Consiglio Nazionale delle Ricerche (CNR), Naples 80131, Italy., Rossi G; Department of Life, Health, and Environmental Sciences, Università dell'Aquila, L'Aquila 67100, Italy., Hay Mele B; Department of Biology, University of Naples 'Federico II,' Napoli 80126, Italy., Acurzio B; Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli,' Caserta 81100, Italy., Coonrod S; Baker Institute for Animal Health, Cornell University, Ithaca, New York 14853, USA., Cubellis MV; Department of Biology, University of Naples 'Federico II,' Napoli 80126, Italy., Cerrato F; Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli,' Caserta 81100, Italy., Andrews S; Bioinformatics Unit, The Babraham Institute, Cambridge CB22 3AT, United Kingdom., Cecconi S; Department of Life, Health, and Environmental Sciences, Università dell'Aquila, L'Aquila 67100, Italy., Kelsey G; Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom; andrea.riccio@unicampania.it gavin.kelsey@babraham.ac.uk.; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom.; Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge CB2 0QQ, United Kingdom., Riccio A; Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli,' Caserta 81100, Italy; andrea.riccio@unicampania.it gavin.kelsey@babraham.ac.uk.; Institute of Genetics and Biophysics (IGB) 'Adriano Buzzati-Traverso,' Consiglio Nazionale delle Ricerche (CNR), Naples 80131, Italy.
Jazyk:	angličtina
Zdroj:	Genes & development [Genes Dev] 2024 Mar 22; Vol. 38 (3-4), pp. 131-150. Date of Electronic Publication: 2024 Mar 22.
DOI:	10.1101/gad.351238.123
Abstrakt:	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 Padi6 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 Padi6 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 Padi6 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. (© 2024 Giaccari et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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