Histone Deacetylase 2 (HDAC2) Regulates Chromosome Segregation and Kinetochore Function via H4K16 Deacetylation during Oocyte Maturation in Mouse

Pengpeng Ma,Richard M Schultz,Martin M Matzuk

doi:10.1371/journal.pgen.1003377

Abstract

Changes in histone acetylation occur during oocyte development and maturation, but the role of specific histone deacetylases in these processes is poorly defined. We report here that mice harboring Hdac1 −/+/Hdac2 −/− or Hdac2 −/− oocytes are infertile or sub-fertile, respectively. Depleting maternal HDAC2 results in hyperacetylation of H4K16 as determined by immunocytochemistry—normal deacetylation of other lysine residues of histone H3 or H4 is observed—and defective chromosome condensation and segregation during oocyte maturation occurs in a sub-population of oocytes. The resulting increased incidence of aneuploidy likely accounts for the observed sub-fertility of mice harboring Hdac2 −/− oocytes. The infertility of mice harboring Hdac1 −/+/Hdac2 −/−oocytes is attributed to failure of those few eggs that properly mature to metaphase II to initiate DNA replication following fertilization. The increased amount of acetylated H4K16 likely impairs kinetochore function in oocytes lacking HDAC2 because kinetochores in mutant oocytes are less able to form cold-stable microtubule attachments and less CENP-A is located at the centromere. These results implicate HDAC2 as the major HDAC that regulates global histone acetylation during oocyte development and, furthermore, suggest HDAC2 is largely responsible for the deacetylation of H4K16 during maturation. In addition, the results provide additional support that histone deacetylation that occurs during oocyte maturation is critical for proper chromosome segregation.

Highlights

Post-translational modifications of histones, e.g., phosphorylation, methylation, ubiquitination, and acetylation, are critically involved in a number of cellular processes that range from regulating gene expression to repair of DNA damage [1,2,3]
Oocyte development is becoming of increasing interest in the broad research community and within the general public due, in part, to the ever increasing demand for and use of assisted reproductive technologies (ART) to treat human infertility, and because the oocyte-toembryo transition encompasses a natural reprogramming of gene expression, a process central to forming iPS cells
We previously found that ovarian weight in 6-week-old-mice was reduced by,60% in Hdac12/+/Hdac22/2 mice and by,70% in Hdac1:22/2 mice compared to wild-type (WT) mice [14]

Summary

Introduction

Post-translational modifications of histones, e.g., phosphorylation, methylation, ubiquitination, and acetylation, are critically involved in a number of cellular processes that range from regulating gene expression to repair of DNA damage [1,2,3]. Results of other studies support the notion that HDAC1 and HDAC2 have distinct functions in some cells and tissues [10,11,12,13]. Mice in which Hdac22/2 was only deleted in oocytes are sub-fertile despite increased amounts of HDAC1 protein whereas their Hdac12/+/Hdac22/2 counterparts are infertile [14]. Taken together, these results suggest a more prominent role for HDAC2 than HDAC1 in oocyte development, whereas HDAC1 plays a more prominent role in preimplantation development [13]. The molecular basis for the sub-fertility of mice harboring Hdac22/2 oocytes or infertility of mice harboring Hdac12/+/Hdac22/2, was not examined

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Discussion

Conclusion