Chromosome Cohesion Established by Rec8-Cohesin in Fetal Oocytes Is Maintained without Detectable Turnover in Oocytes Arrested for Months in Mice

Abstract

SummarySister chromatid cohesion mediated by the cohesin complex is essential for chromosome segregation in mitosis and meiosis [1]. Rec8-containing cohesin, bound to Smc3/Smc1α or Smc3/Smc1β, maintains bivalent cohesion in mammalian meiosis [2, 3, 4, 5, 6]. In females, meiotic DNA replication and recombination occur in fetal oocytes. After birth, oocytes arrest at the prolonged dictyate stage until recruited to grow into mature oocytes that divide at ovulation. How cohesion is maintained in arrested oocytes remains a pivotal question relevant to maternal age-related aneuploidy. Hypothetically, cohesin turnover regenerates cohesion in oocytes. Evidence for post-replicative cohesion establishment mechanism exists, in yeast and invertebrates [7, 8]. In mouse fetal oocytes, cohesin loading factor Nipbl/Scc2 localizes to chromosome axes during recombination [9, 10]. Alternatively, cohesion is maintained without turnover. Consistent with this, cohesion maintenance does not require Smc1β transcription, but unlike Rec8, Smc1β is not required for establishing bivalent cohesion [11, 12]. Rec8 maintains cohesion without turnover during weeks of oocyte growth [3]. Whether the same applies to months or decades of arrest is unknown. Here, we test whether Rec8 activated in arrested mouse oocytes builds cohesion revealed by TEV cleavage and live-cell imaging. Rec8 establishes cohesion when activated during DNA replication in fetal oocytes using tamoxifen-inducible Cre. In contrast, no new cohesion is detected when Rec8 is activated in arrested oocytes by tamoxifen despite cohesin synthesis. We conclude that cohesion established in fetal oocytes is maintained for months without detectable turnover in dictyate-arrested oocytes. This implies that women’s fertility depends on the longevity of cohesin proteins that established cohesion in utero.

Long-Term Retention of CENP-A Nucleosomes in Mammalian Oocytes Underpins Transgenerational Inheritance of Centromere Identity

“…2B, model 2). Similarly, cohesion is established in pre-meiotic S-phase without detectable cohesin turnover during prophase I [17]. Further, both the WT and KO groups retain ~70% of the CENP-A protein seen in the young C57BL/6J group, showing that the majority of CENP-A present since early prophase I arrest in the primordial follicle is retained at the centromere for ~1 year.…”

Dynamic and Stable Cohesins Regulate Synaptonemal Complex Assembly and Chromosome Segregation

“…In contrast, centromeric SOLO/SUNN can only be loaded prior to meiotic prophase. Sister-chromatid cohesion in mitotic cells is established during S-phase [36] and in mammals, Rec8 cohesin cannot be replenished and dissociates with age [15, 16, 37]. Whereas in mitotic cells the dynamic and stable cohesin complexes involve the same four core subunits, in meiosis, there may be separate cohesin complexes that differ in their regulation and capacity to be replaced or replenished.…”

A mechanism of cohesin‐dependent loop extrusion organizes zygotic genome architecture

“…We have previously shown that Scc1 protein is efficiently depleted and sister chromatid cohesion fails to be established in Scc1 Δ(m)/+(p) zygotes (hereafter referred to as Scc1 Δ according to the maternal allele; see Fig EV3B and Ladstätter & Tachibana-Konwalski, 2016). Since sister chromatid cohesion is maintained by Rec8-cohesin in oocytes (Tachibana-Konwalski et al, 2010;Burkhardt et al, 2016), Scc1 depletion has no effect on chromosome segregation prior to fertilization, and therefore, a clean Scc1-cohesin knockout zygote is generated.…”