Inhibition of neddylation disturbs zygotic genome activation through histone modification change and leads to early...

Area of Science:

• Developmental Biology
• Epigenetics
• Molecular Biology

Background:

• Post-translational modifications and protein turnover are crucial for mammalian early embryo development.
• Ubiquitination-like modifications, such as neddylation, play roles yet to be fully elucidated in this process.

Purpose of the Study:

• To investigate the function and mechanisms of neddylation in mouse preimplantation embryo development.
• To understand how neddylation inhibition affects gene expression and epigenetic modifications.

Main Methods:

• Treatment of zygotes with specific neddylation inhibitors.
• Transcriptional profiling to analyze gene expression changes.
• Proteomic analysis to identify differentially expressed proteins.
• Analysis of histone modifications (H3K4me3, H3K27ac) and key signaling pathway components (YAP1, RPL13).

Main Results:

• Neddylation inhibition significantly decreased zygote cleavage rates and hindered progression to the 4-cell stage.
• Differential gene expression was observed in pathways related to cell fate determination and differentiation, including down-regulated zygotic genome activation (ZGA) markers.
• Impaired gene transcription was indicated by decreased phosphorylated RNA polymerase II.
• Proteomic data revealed enrichment of differentially expressed proteins in histone modifications, with decreased KMT2D, H3K4me3, CBP/p300, and H3K27ac, and increased HDAC6.
• Up-regulation of YAP1 and RPL13 activities suggested Hippo signaling pathway abnormalities.

Conclusions:

• Inhibition of neddylation in early embryos induces significant epigenetic changes and leads to abnormalities in critical downstream signaling pathways.
• These findings highlight the role of neddylation as a key regulator in mammalian embryonic development and suggest its potential involvement in female infertility pathology.