Tower Catherine A, Manske Gabriel, Ferrell Emily L, Anbarci Dilara N, Jorgensen Kelsey, Ma Binbin, Aboelenain Mansour, Ranjan Rajesh, Chakraborty Saikat, Moritz Lindsay, Das Arunika, Boiani Michele, Black Ben E, Chavez Shawn, Marsh Erica E, Shikanov Ariella, Schindler Karen, Chen Xin, Hammoud Saher Sue
bioRxiv. 2025 Jul 28:2025.07.23.666394. doi: 10.1101/2025.07.23.666394.
Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation at the parental-to-zygote transition in mammals is poorly understood. To address this, we developed a CENP-A-mScarlet knock-in mouse model, which revealed sex-specific dynamics: mature sperm retains 10% of the CENP-A levels present in MII-oocytes. However, in zygotes prior to the first mitosis, this difference is resolved, using maternally inherited cytoplasmic-CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization domains impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity.
CENP-A asymmetry between sperm and oocyte centromeres is a conserved feature from flies to mammals including mice and humans.CENP-A asymmetry between parental centromeres is resolved prior to the first zygotic division via maternally inherited, cytoplasmic CENP-A.Zygotic CENP-A levels in zygotes are regulated in a pronucleus-autonomous manner.CENP-A equalization relies on asymmetric CENP-C recruitment to the paternal pronucleus and requires CENP-C dimerization.
Centromere; CENP-A; CENP-C; sperm; oocyte; zygote; intergenerational; epigenetics; mouse.
在多细胞动物物种中，着丝粒特异性组蛋白变体CENP - A对于准确的染色体分离至关重要，然而其在哺乳动物从亲代到合子转变过程中的调控机制却知之甚少。为了解决这个问题，我们开发了一种CENP - A - mScarlet基因敲入小鼠模型，该模型揭示了性别特异性动态变化：成熟精子保留了MII期卵母细胞中10%的CENP - A水平。然而，在第一次有丝分裂之前的合子中，这种差异通过母源遗传的细胞质CENP - A得以解决。值得注意的是，父本着丝粒处CENP - A的增加独立于对CENP - A不对称性的感知或母源染色体的存在。相反，CENP - A的平衡依赖于母源CENP - C向父本着丝粒的不对称招募。母源CENP - A的缺失会降低原核中总CENP - A水平，但不会破坏平衡。相比之下，减少母源CENP - C或破坏其二聚化结构域会损害CENP - A的平衡和染色体分离。因此，母源CENP - C作为一种关键的表观遗传调节因子，在受精时重置着丝粒对称性以维持基因组完整性。
精子和卵母细胞着丝粒之间的CENP - A不对称性是从果蝇到包括小鼠和人类在内的哺乳动物的一个保守特征。亲代着丝粒之间的CENP - A不对称性在合子的第一次分裂之前通过母源遗传的细胞质CENP - A得以解决。合子中的合子CENP - A水平以原核自主的方式受到调控。CENP - A的平衡依赖于CENP - C向父本原核的不对称招募，并且需要CENP - C二聚化。
着丝粒；CENP - A；CENP - C；精子；卵母细胞；合子；代际；表观遗传学；小鼠
