Abstract
Sirt6, a member of the sirtuin family of NAD-dependent protein deacetylases, has been implicated in multiple biological processes. However, the roles of Sirt6 in meiosis have not been addressed. In the present study, by employing knockdown analysis in mouse oocytes, we evaluated the effects of Sirt6 on meiotic apparatus. We found that specific depletion of Sirt6 results in disruption of spindle morphology and chromosome alignment in oocytes. Consistent with this observation, incidence of aneuploidy is also markedly increased in Sirt6-depleted oocytes. Furthermore, confocal scanning showed that kinetochore-microtubule interaction, an important mechanism controlling chromosome segregation, is severely impaired in metaphase oocytes following Sirt6 knockdown. Unexpectedly, we discovered that Sirt6 modulates the acetylation status of histone H4K16 as their knockdown specifically induces the hyperacetylation of H4K16 in oocytes, which may be associated with the defective phenotypes described above via altering kinetochore function. Altogether, our data reveal a novel function of Sirt6 during oocyte meiosis and indicate a pathway regulating meiotic apparatus.
Highlights
Regulating cellular metabolism, aging, and apoptosis[7]
The results indicate that Sirt[6] may be a chromatin-associated protein in mouse oocytes, which is consistent with the data in somatic cells[11]
Sirt[6] is a chromatin-associated protein that possesses the activity of ADP-ribosylase and NAD+-dependent deacetylase[28], modulating chromatin accessibility and gene expression[15]
Summary
Regulating cellular metabolism, aging, and apoptosis[7]. For example, Sirt[1] physically interacts with p53 and attenuates p53-mediated DNA damage-induced apoptotic response[8]. Mostoslavsky et al found that Sirt[6] was a chromatin-associated protein, promoting resistance to DNA damage and suppressing genomic instability in mouse cells[11]. Sirt[6] has been demonstrated to be a NAD+-dependent histone deacetylase. Through deacetylating histone H3 lysine 9 (H3K9), Sirt[6] participates in the regulation of telomeric chromatin and cellular senescence in human U2O cells[12]. Histone H3 lysine 56 (H3K56) was indicated as an enzymatic substrate of Sirt[6] in other cell types[13,14]. Sirt6-mediated deacetylation of H3K56 decreases chromatin accessibility for transcription factors such as NF-kB, Foxo[3], and HIF1α to their respective target promoters, thereby inhibiting the expression of their target genes[15]. By employing morpholino knockdown, we found that Sirt[6] depletion adversely impacts the maturational progression, spindle organization, and chromosome alignment in mouse oocytes
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