Results for “Subcortical maternal complex”

PubMed2025

The subcortical maternal complex safeguards mouse oocyte-to-embryo transition by preventing nuclear entry of SPIN1.

How cytoplasmic regulators control nuclear events in mammalian oocytes and early embryos remains largely enigmatic. We previously identified a subcortical maternal complex (SCMC) that specifically resides in the cytoplasm of mammalian oocytes and early embryos but is also involved in nuclear events. Nevertheless, how the cytoplasmic SCMC exerts its role in nuclear processes remains unknown. In this study, we unveil SPIN1, a histone methylation reader, as a novel member of the SCMC. The SCMC component FILIA tightly regulates the expression and cytoplasmic localization of SPIN1 through direct interaction. When the expression of FILIA is decreased because of genetic mutations of SCMC genes, SPIN1 expression is dramatically reduced but the residual SPIN1 translocates into the nucleus. The abnormal nuclear presence of SPIN1 impairs H3K4me3 reprogramming, zygotic genome activation and physiological embryonic development. Inhibiting the interaction between SPIN1 and H3K4me3 partially rescues the abnormal phenotype in FILIA-null embryos. Mechanistically, SPIN1 partially perturbs the demethylation process by competing with KDM5B for binding to H3K4me3. Collectively, our work highlights the complexity of the mammalian SCMC and oocyte-to-embryo transition, revealing an intricate regulatory mechanism that facilitates the smooth progression of this process.

Animals↗

PubMed2026

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

BACKGROUND: 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. RESULTS: By employing combined single-blastocyst RNA-seq/BS-seq and immunostaining validation in the embryos derived from Padi6P620A-mutant oocytes, we investigated the role of Padi6 in late preimplantation development. We demonstrated that embryos that overcame the two-cell stage block had a dramatic reduction in UHRF1 and DNMT1 protein levels, a decrease in H3K9me3, and whole-genome hypomethylation, including most imprinted loci and repetitive elements, at the blastocyst stage. Furthermore, these maternal mutant embryos showed deregulation of inner cell mass markers and defective blastocyst implantation, but no effect on trophoblast differentiation. CONCLUSION: Our results demonstrate that maternal PADI6 is a key regulator of the stability of epigenetic factors required to maintain repressive marks in late preimplantation mouse embryos. Its deficiency results in genomic imprinting defects that closely resemble those found in human patients and provide a mechanistic explanation for MLID caused by maternal PADI6 variants. Furthermore, the impairment of blastocyst implantation capacity, likely due to dysregulation of inner cell mass differentiation, provides new mechanistic insights into the control of female fertility and embryo development exerted by PADI6.

DNA Methylation↗