Nucleocytoplasmic shuttling of sirtuin 1 regulates histone modifications and transcriptional events during early porcine embryonic development

The precise resetting and establishment of epigenomes are meticulously coordinated processes indispensable for successful embryogenesis. Sirtuin 1 (SIRT1), a NAD-dependent protein deacetylase, serves as a pivotal regulator within cellular signaling networks and a myriad of biological pathways. Its subcellular localization critically dictates its role as an epigenetic modifier. Here, we identified SIRT1 exhibits dynamic nucleocytoplasmic shuttling during early porcine embryonic development, tightly aligning with key developmental stages. SIRT1 is predominantly localized in the nucleus from the 1-cell to 2-cell stages, shifting to the cytoplasm from the 4-cell stage onward. Deficiency in SIRT1 or inhibition of PCAF disrupts histone H3 lysine trimethylation (H3K9me3) and acetylation (H3K9ac), thereby impairing zygotic genome activation transcription. Furthermore, SIRT1 deficiency compromises SUV39H1 transcription site accessibility, implicating PCAF-mediated EZH2 recruitment for transcriptional repression. At later stages, cytoplasmic SIRT1 facilitates SUV39H1 ubiquitination, notably in blastocysts, emphasizing its multifunctional regulatory roles. These findings highlight SIRT1's critical role as a spatiotemporal regulator, where its nucleocytoplasmic shuttling precisely modulates epigenetic changes, coordinates genome activation, and steers embryonic development through spatially coordinated SIRT1-mediated PCAF modulation of SUV39H1 activity.

Embryonic development; Histone methylation; Nucleocytoplasmic shuttling; PCAF; SIRT1; Zygotic genome activation.