HDAC3 promotes meiotic apparatus assembly in mouse oocytes by modulating tubulin acetylation

Abstract

Histone deacetylases (HDACs) have been shown to deacetylate numerous cellular substrates that govern a wide array of biological processes. HDAC3, a member of the Class I HDACs, is a highly conserved and ubiquitously expressed protein. However, its roles in meiotic oocytes are not known. In the present study, we find that mouse oocytes depleted of HDAC3 are unable to completely progress through meiosis, and are blocked at metaphase I. These HDAC3 knockdown oocytes show spindle/chromosome organization failure, with severely impaired kinetochore-microtubule attachments. Consistent with this, the level of BubR1, a central component of the spindle assembly checkpoint, at kinetochores is dramatically increased in metaphase oocytes following HDAC3 depletion. Knockdown and overexpression experiments reveal that HDAC3 modulates the acetylation status of α-tubulin in mouse oocytes. Importantly, the deacetylation mimetic mutant tubulin-K40R can partly rescue the defective phenotypes of HDAC3 knockdown oocytes. Our data support a model whereby HDAC3, through deacetylating tubulin, promotes microtubule stability and the establishment of kinetochore-microtubule interaction, consequently ensuring proper spindle morphology, accurate chromosome movement and orderly meiotic progression during oocyte maturation.

Loss of HDAC3 contributes to meiotic defects in aged oocytes

“…Given that the oocytes depleted of HDAC3 displayed the similar phenotypes as those from aged mice (Li et al, ), we decided to determine the HDAC3 expression in oocytes from young (3 weeks of age) and old (42 weeks of age) mice by Western blot analysis. As shown in Figure a‐b, a remarkable reduction of HDAC3 protein was detected in germinal vesicle (GV) stage oocytes from old mice compared to that from young mice.…”

NMNAT2‐mediated NAD+ generation is essential for quality control of aged oocytes

“…Chromosome preparations for MII oocytes were performed as described previously (Li et al, ). MII oocytes were exposed to Tyrode's buffer (pH 2.5) for 30 s at 37°C to remove zona pellucida.…”

Listening to mother: Long‐term maternal effects in mammalian development

“…Inadequate histone deacetylation is associated with increased aneuploidy, aberrant oocyte meiosis (Huang et al, 2012; Ma & Schultz, 2013, 2016), and with reduced oocyte quality accompanying aging (van den Berg et al, 2011). Histone deacetylases also regulate the activities of other proteins, and inhibition of this process can also disrupt spindle formation in mitotic and meiotic cells (Chuang, Pan, Hawke, Lin, & Yu‐Lee, 2013; Gabrielli & Brown, 2012; X. Li et al, 2017; Shin et al, 2003). Excess histone acetylation may account in part for increased rates of aneuploidy seen in cloned constructs made by transferring somatic cell nuclei to oocytes (Mizutani et al, 2012; Nolen et al, 2005).…”