Centromere-specifying nucleosomes persist in aging mouse oocytes in the absence of nascent assembly

Centromeres direct genetic inheritance but are not themselves genetically encoded. Instead, centromeres are defined epigenetically by the presence of a histone H3 variant, CENP-A. 1 Kixmoeller K. Allu P.K. Black B.E. The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle. Open Biol. 2020; 10200051https://doi.org/10.1098/rsob.200051 Crossref PubMed Scopus (36) Google Scholar In cultured somatic cells, an established paradigm of cell-cycle-coupled propagation maintains centromere identity: CENP-A is partitioned between sisters during replication and replenished by new assembly, which is restricted to G1. The mammalian female germ line challenges this model because of the cell-cycle arrest between pre-meiotic S phase and the subsequent G1, which can last for the entire reproductive lifespan (months to decades). New CENP-A chromatin assembly maintains centromeres during prophase I in worm and starfish oocytes, 2 Prosée R.F. Wenda J.M. Özdemir I. Gabus C. Delaney K. Schwager F. Gotta M. Steiner F.A. Transgenerational inheritance of centromere identity requires the CENP-A N-terminal tail in the C. elegans maternal germ line. PLoS Biol. 2021; 19e3000968https://doi.org/10.1371/journal.pbio.3000968 Crossref PubMed Scopus (7) Google Scholar ,3 Swartz S.Z. McKay L.S. Su K.-C. Bury L. Padeganeh A. Maddox P.S. Knouse K.A. Cheeseman I.M. Quiescent cells actively replenish CENP-A nucleosomes to maintain centromere identity and proliferative potential. Dev. Cell. 2019; 51: 35-48.e7https://doi.org/10.1016/j.devcel.2019.07.016 Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar suggesting that a similar process may be required for centromere inheritance in mammals. To test this hypothesis, we developed an oocyte-specific conditional knockout (cKO) mouse for Mis18α, an essential component of the assembly machinery. We find that embryos derived from Mis18α knockout oocytes fail to assemble CENP-A nucleosomes prior to zygotic genome activation (ZGA), validating the knockout model. We show that deletion of Mis18α in the female germ line at the time of birth has no impact on centromeric CENP-A nucleosome abundance, even after 6–8 months of aging. In addition, there is no detectable detriment to fertility. Thus, centromere chromatin is maintained long-term, independent of new assembly during the extended prophase I arrest in mouse oocytes.