Differential condensation of sister chromatids acts with Cdc6 to ensure asynchronous S-phase entry in Drosophila male germline stem cell lineage

During Drosophila melanogaster male GSC (germline stem cell) asymmetric division, preexisting old versus newly synthesized histones H3 and H4 are asymmetrically inherited. However, the biological outcomes of this phenomenon remained unclear. Here, we tracked old and new histones throughout the GSC cell cycle using high spatial and temporal resolution microscopy. We found unique features that differ between old and new histone-enriched sister chromatids, including differences in nucleosome density, chromosomal condensation, and H3 Ser10 phosphorylation. These distinct chromosomal features lead to their differential association with Cdc6, a pre-replication complex component, and subsequent asynchronous DNA replication initiation in the resulting daughter cells. Disruption of asymmetric histone inheritance abolishes differential Cdc6 association and asynchronous S-phase entry, demonstrating that histone asymmetry acts upstream of these critical cell cycle progression events. Furthermore, disruption of these GSC-specific chromatin features leads to GSC defects, indicating a connection between histone inheritance, cell cycle progression, and cell fate determination.

在黑腹果蝇的雄性生殖干细胞（germline stem cell，GSC）的非对称分裂过程中，原有的旧型与新生成的组蛋白H3和H4呈现非对称遗传。然而，这一现象的生物学后果尚不明确。本研究中，我们利用高时空分辨率的显微镜追踪了GSC细胞周期中的旧型和新生成组蛋白，发现旧型与新生成组蛋白富集的姐妹染色单体之间存在独特特征，包括核小体重密度、染色体凝缩以及H3 Ser10磷酸化等方面的差异。这些独特的染色体特征导致了它们与Cdc6（一个复制前复合体组分）的差异化结合，以及后续子细胞中异步的DNA复制起始。破坏非对称的组蛋白遗传导致Cdc6的差异化结合及异步S期进入消失，证明组蛋白非对称性作用于这些关键细胞周期进程事件的上游。此外，破坏这些生殖干细胞特异的染色质特征会导致GSC缺陷，表明组蛋白遗传、细胞周期进程以及细胞命运决定之间存在联系。