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Loss of maternal PADI6 disrupts DNA methylation and genomic imprinting maintenance in late preimplantation mouse embryos

ABSTRACT: The maternal-effect protein PADI6, which is part of the subcortical maternal complex, is involved in proper spindle assembly, organelle distribution, ribosome storage, and cytoplasmic lattice organization in mouse oocytes. In humans, variants of PADI6 are associated with female infertility and multilocus imprinting disturbance in offspring. Recently, it was demonstrated that PADI6 plays a role in the storage and cytoplasmic localization of epigenetic factors, including UHRF1 and DNMT1. Moreover, maternal PADI6 depletion leads to defective epigenetic reprogramming and zygotic genome activation but not to an imprinting defect in two-cell mouse embryos. These findings raise the possibility that imprinting disturbances arise later in development.

ORGANISM(S): Mus musculus

PROVIDER: GSE316341 | GEO | 2026/06/03

REPOSITORIES: GEO

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Loss of maternal PADI6 disrupts DNA methylation and genomic imprinting maintenance in late preimplantation mouse embryos.

Project description:The maternal-effect protein PADI6, which is part of the subcortical maternal complex, is involved in proper spindle assembly, organelle distribution, ribosome storage, and cytoplasmic lattice organization in mouse oocytes. In humans, variants of PADI6 are associated with female infertility and multilocus imprinting disturbance in offspring. Recently, it was demonstrated that PADI6 plays a role in the storage and cytoplasmic localization of epigenetic factors, including UHRF1 and DNMT1. Moreover, maternal PADI6 depletion leads to defective epigenetic reprogramming and zygotic genome activation but not to an imprinting defect in two-cell mouse embryos. These findings raise the possibility that imprinting disturbances arise later in development.

2026-06-03 | GSE316549 | GEO

Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann Syndrome with multi-locus imprinting disturbance

Project description:PADI6 is a component of the subcortical maternal complex (SCMC) which is a group of proteins that are abundantly expressed in the oocyte cytoplasm and essential for the proper development of the early embryo. The mutation(s) in the components of the subcortical maternal complex have been associated with reproductive failures, including formation of hydatidiform mole, female infertility and imprinting disorders with multi-locus imprinting disturbance (MLIDs).In the current study by using whole-exome sequencing analysis, we identified four cases of Beckwith-Wiedemann Syndrome with multi-locus imprinting disturbance while their mothers were carriers of variants in PADI6 gene. Genome-wide methylation profiling using Methylation EPIC array depicted the loss of methylation specifically at several known imprinted loci in affected individuals as compared to healthy siblings, parents and controls. Our findings firmly establish the role of PADI6 in imprinting disorders.

2020-10-02 | GSE153211 | GEO

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 [WGS]

Project description:Maternal inactivation of genes encoding components of the sub-cortical 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 multi-locus 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 2-cell stage. Single-cell multi-omic 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 2-cell embryos developing from Padi6-mutant oocytes, but little effect on genomic imprinting. Western blotting and immunofluorescence analyses showed reduced level 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 pre-implantation epigenetic reprogramming and ZGA.

2023-10-18 | GSE245425 | GEO

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 [scBS-seq]

2023-10-18 | GSE245424 | GEO

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 [scRNA-seq]

2023-10-18 | GSE245423 | GEO

An Nlrp5-null mutation leads to attenuated de novo methylation in oocytes, accompanied by significant reduction in DNMT3L

Project description:Nlrp5 encodes a core component of the subcortical maternal complex (SCMC) a cytoplasmic protein structure unique to the mammalian oocyte and cleavage-stage embryo. NLRP5 mutations have been identified in patients presenting with early embryo arrest, recurrent molar pregnancies and imprinting disorders. It was previously shown that oocytes with mutations in the human SCMC gene KHDC3L had globally impaired methylation, suggesting a requirement for integrity of the SCMC in the establishment of DNA methylation. Here, we present a multi-omic analysis of an Nlrp5-null mouse model. We detect global misregulation of maternal proteins, including profound reduction in the essential de novo methylation factor DNMT3L, which could contribute to attenuated de novo methylation we observe. In contrast, the maintenance methyltransferase DNMT1 exhibits normal cytoplasmic localisation. This provides evidence for mechanisms leading to downstream misregulation of imprinted genes, which in turn, may result in imprinting syndromes, multi-locus imprinting disturbances (MLID) and hydatidiform moles.

2025-12-22 | PXD056859 | Pride

Mammalian oocytes store proteins in cytoplasmic lattices

Project description:Oocytes must accumulate and store maternal factors such as proteins during growth to sustain the first stages of embryonic development. How mammalian oocytes store maternal proteins is not understood. Here, we show that mouse and human oocytes store proteins on cytoplasmic lattices. With super-resolution light microscopy and electron tomography, we demonstrate that cytoplasmic lattices are twisted filament bundles formed by proteins of the subcortical maternal complex, filling the entire ooplasm. The lattices were associated with many proteins that have crucial functions during early embryo development, including proteins controlling genome methylation. Loss of cytoplasmic lattices prevented the accumulation of these proteins and resulted in early embryonic arrest. Thus, cytoplasmic lattices are important for storage of essential maternal proteins and the developmental success of early mammalian embryos.

2023-10-23 | PXD038575 | Pride

Dissecting PADI6 function defines oocyte cytoplasmic lattices as regulatory hubs for fundamental cellular processes

Project description:Transcriptome profiling of MII oocytes, zygote and 2-cell embryos (processed as individual blastomeres) from wild-type females, females with a single point mutation in Padi6 resulting in the amino acid substitution C663A (Padi6-C663A), and females with a Padi6 null mutation (Padi6-KO).

2025-02-23 | GSE289965 | GEO

Characterization of the components of mouse cytoplasmic lattice

Project description:The fertilized egg relies almost entirely on maternal stores in the oocyte to ensure the successful initiation of development. The cytoplasmic lattices (CPLs) in mammalian oocytes store maternal-expressed proteins and play an essential role in embryogenesis. Impairing multiple CPL members leads to early embryonic arrest (EEA), resulting in infertility in mammals. However, the mechanism underlying the assembly and storage of CPLs remains largely unknown. Here, we report the cryo-EM structure of a native mouse CPL repeating unit (~ 4 MDa) at 3.74 Å resolution. This repeating unit exhibits a tripartite architecture comprising a framework, extended linkers, and a CPL core. The external framework is built from PADI6 decamers and the subcortical maternal complexes (SCMC). Two linkers formed by NLRP4F polymerize the frameworks into an extended filament. In CPL core, the epigenetic regulator UHRF1 is trapped by PADI6, UBE2D, and NLRP14 in a compact, autoinhibited conformation that prevents nuclear entry and ubiquitin ligase activity. Moreover, the CPL core stores GTP-bound α/β-tubulin heterodimers and inactive SCF E3-ubiquitin ligase components (FBXW-SKP1 complex) in a poised but restrained state. These features establish CPLs as a dynamic regulatory pool that enables rapid microtubule assembly and tightly controlled ubiquitination during the oocyte-to-embryo transition. Together, this semi-in-situ structure illuminates CPL assembly and storage-module organization, and establishes CPLs as specialized proteostasis organelles for maternal regulation in oocytes and early embryonic development.

2026-02-10 | PXD074322 |

Cytoplasmic lattices are megadalton storage complexes for tubulin and ubiquitination factors in mammalian oocytes

Project description:Mammalian oocytes store proteins for embryonic development on abundant structures known as cytoplasmic lattices (CPLs); however, the mechanisms by which they achieve this are unclear, largely because the molecular composition of the lattices themselves is unknown. Here, we use cryo-electron microscopy and artificial intelligence-based modeling to elucidate the molecular architecture and protein composition of native CPLs from mouse oocytes. We find that CPLs are formed by at least 13 different proteins assembling into a megadalton-scale complex, including multiple copies of maternal effect factors such as PADI6 and the subcortical maternal complex (SCMC). We show that proteins essential for early embryonic development are in fact structural components of the CPLs, including the cytoskeletal proteins α- and β-tubulin, which are incorporated into CPLs as unpolymerized dimers; and an array of ubiquitination factors such as the epigenetic regulator and E3 ligase UHRF1, ubiquitin-conjugating E2 enzymes, and ubiquitin ligase substrate adaptors. This represents an elegant molecular mechanism by which oocytes stockpile vital proteins through direct incorporation into highly stable supramolecular assemblies. Our structures solve the decades-long mystery of the CPLs, thereby providing a structural framework for understanding how disrupting stored maternal factors leads to infertility and developmental defects.

2026-03-11 | PXD073451 | Pride

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