Asymmetric partition of parental histone (H3-H4)2 tetramers onto replicating DNA strands

In eukaryotic cells, inheritable changes in gene expression in response to environmental and developmental stimuli is associated with changes in histone modifications and relies on the passage of these changes into daughter cells during cell division, a process that remains elusive. Here, we show that parental histone (H3-H4)2 tetramers, the primary carrier of epigenetic modifications, are assembled into nucleosomes onto both replicating leading and lagging strands, with a preference for lagging strands of DNA replication forks. This asymmetric distribution of parental (H3-H4)2 is exacerbated in cells lacking Dpb3 and Dpb4, two subunits of DNA polymerase Pol ε. Dpb3-Dpb4 binds (H3-H4)2 and participates in the transfer of parental (H3-H4)2 tetramers onto leading strands of DNA replication forks. Cells lacking Dpb3 and Dpb4 exhibits defects in epigenetic inheritance. These results reveal a previously undocumented mechanism of histone segregation and a direct role for Pol ε in this poorly understood process.在真核细胞中，响应环境与发育刺激所产生的基因表达可遗传改变，与组蛋白修饰（histone modification）的变化紧密关联，且依赖于这类改变在细胞分裂过程中传递至子代细胞——这一过程目前仍未被完全阐明。本研究证实，作为表观遗传修饰（epigenetic modification）的主要载体，亲本组蛋白(H3-H4)2四聚体可组装进入复制中的前导链与后随链所在的核小体（nucleosome），且对DNA复制叉的后随链存在偏好性。在缺失DNA聚合酶Pol ε的两个亚基Dpb3与Dpb4的细胞中，亲本(H3-H4)2的这种不对称分布会进一步加剧。Dpb3-Dpb4复合物可结合(H3-H4)2四聚体，并参与将亲本(H3-H4)2四聚体转运至DNA复制叉的前导链上。缺失Dpb3与Dpb4的细胞会出现表观遗传继承缺陷。上述研究结果揭示了一种此前未被报道的组蛋白分离机制，以及DNA聚合酶Pol ε在这一研究尚不充分的过程中的直接作用。