Differential condensation of sister chromatids acts with Cdc6 to ensure distinct cell cycle progression 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（GSC）的不对称分裂过程中，预先存在的老化的组蛋白H3与新生成的组蛋白H4呈现出不对称的遗传。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细胞周期中老化和新生组蛋白的动态变化。我们发现，老化与新生组蛋白富集的姐妹染色单体之间存在独特的差异，包括核小体密度、染色体凝聚以及H3 Ser10磷酸化的不同。这些独特的染色体特征导致了它们与Cdc6（一种复制前复合体组分）的不同结合，进而引发了后代细胞中DNA复制启动的异步进行。破坏不对称的组蛋白遗传导致Cdc6结合差异和S期进入的异步性消失，这表明组蛋白的不对称性作用于这些关键的细胞周期进程事件的上游。此外，破坏这些生殖干细胞特有的染色质特征会导致GSC缺陷，这表明组蛋白遗传、细胞周期进程和细胞命运决定之间存在联系。