Department of Biochemistry and Biophysics; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
Nat Cell Biol. 2022 May;24(5):748-756. doi: 10.1038/s41556-022-00897-w. Epub 2022 May 9.
Centromeres are defined epigenetically by the histone H3 variant CENP-A. The propagation cycle by which pre-existing CENP-A nucleosomes serve as templates for nascent assembly predicts the epigenetic memory of weakened centromeres. Using a mouse model with reduced levels of CENP-A nucleosomes, we find that an embryonic plastic phase precedes epigenetic memory through development. During this phase, nascent CENP-A nucleosome assembly depends on the maternal Cenpa genotype rather than the pre-existing template. Weakened centromeres are thus limited to a single generation, and parental epigenetic differences are eliminated by equal assembly on maternal and paternal centromeres. These differences persist, however, when the underlying DNA of parental centromeres differs in repeat abundance, as assembly during the plastic phase also depends on sufficient repetitive centromere DNA. With contributions of centromere DNA and the Cenpa maternal effect, we propose that centromere inheritance naturally minimizes fitness costs associated with weakened centromeres or epigenetic differences between parents.
着丝粒通过组蛋白 H3 变体 CENP-A 进行表观遗传定义。通过先前存在的 CENP-A 核小体作为新生组装模板的繁殖周期预测了减弱的着丝粒的表观遗传记忆。使用 CENP-A 核小体水平降低的小鼠模型，我们发现胚胎塑性阶段先于发育过程中的表观遗传记忆。在此阶段，新生的 CENP-A 核小体组装依赖于母体 Cenpa 基因型，而不是先前存在的模板。因此，弱化的着丝粒仅局限于一代，并且通过在母源和父源着丝粒上进行均等组装消除了亲本的表观遗传差异。然而，当亲本着丝粒的 DNA 在重复丰度上存在差异时，这些差异仍然存在，因为在塑性阶段的组装也取决于足够的重复着丝粒 DNA。由于着丝粒 DNA 和 Cenpa 母性效应的贡献，我们提出了着丝粒遗传自然最小化与弱化的着丝粒或父母之间的表观遗传差异相关的适应成本。
