BACKGROUND: The histone code is an established epigenetic regulator of early embryonic development in mammals. The lysine residue K9 of histone H3 (H3K9) is a prime target of SIRT1, a member of NAD+-dependent histone deacetylase family of enzymes targeting both histone and non-histone substrates. At present, little is known about SIRT1-modulation of H3K9 in zygotic pronuclei and its association with the success of preimplantation embryo development. Therefore, we evaluated the effect of SIRT1 activity on H3K9 methylation and acetylation in porcine zygotes and the significance of H3K9 modifications for early embryonic development. RESULTS: Our results show that SIRT1 activators resveratrol and BML-278 increased H3K9 methylation and suppressed H3K9 acetylation in both the paternal and maternal pronucleus. Inversely, SIRT1 inhibitors nicotinamide and sirtinol suppressed methylation and increased acetylation of pronuclear H3K9. Evaluation of early embryonic development confirmed positive effect of selective SIRT1 activation on blastocyst formation rate (5.2 ± 2.9% versus 32.9 ± 8.1% in vehicle control and BML-278 group, respectively; P ≤ 0.05). Stimulation of SIRT1 activity coincided with fluorometric signal intensity of ooplasmic ubiquitin ligase MDM2, a known substrate of SIRT1 and known limiting factor of epigenome remodeling. CONCLUSIONS: We conclude that SIRT1 modulates zygotic histone code, obviously through direct deacetylation and via non-histone targets resulting in increased H3K9me3. These changes in zygotes lead to more successful pre-implantation embryonic development and, indeed, the specific SIRT1 activation due to BML-278 is beneficial for in vitro embryo production and blastocyst achievement.

Department of Histology and Embryology Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Veterinary Sciences Faculty of Agriculture Food and Natural Resources Czech University of Life Sciences Prague 6 Suchdol Prague Czech Republic

Departments of Obstetrics Gynecology and Women's Health University of Missouri Columbia MO USA

Division of Animal Science University of Missouri Columbia MO USA

Division of Biotechnology Safety Environment and Life Science Institute College of Environmental and Bioresource Sciences Chonbuk National University Iksan 54596 South Korea

Institute of Animal Science 10 Uhrineves Prague Czech Republic

Laboratory of Reproductive Medicine of Biomedical Center Charles University Pilsen Czech Republic

Proteomic Laboratory Biomedical Center of Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

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Dynamics and necessity of SIRT1 for maternal-zygotic transition

Epigenetic and non-epigenetic mode of SIRT1 action during oocyte meiosis progression