Davis Brendon E M, Snedeker Jonathan, Ranjan Rajesh, Wooten Matthew, Barton Savannah Sáde, Blundon Joshua, Chen Xin
Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA.
Howard Hughes Medical Institute, Department of Biology, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA.
Sci Adv. 2025 Feb 28;11(9):eadu6799. doi: 10.1126/sciadv.adu6799.
Stem cells display asymmetric histone inheritance, while nonstem progenitor cells exhibit symmetric patterns in the male germ line. Here, we report that components involved in lagging strand synthesis, DNA polymerases α and δ, have substantially reduced levels in stem cells compared to progenitor cells, and this promotes local asymmetry of parental histone incorporation at the replication fork. Compromising Polα genetically induces the local replication-coupled histone incorporation pattern in progenitor cells to resemble that in stem cells, seen by both nuclear localization patterns and chromatin fibers. This is recapitulated using a Polα inhibitor in a concentration-dependent manner. The local old versus new histone asymmetry is comparable between stem cells and progenitor cells at both S phase and M phase. Together, these results indicate that developmentally programmed expression of key DNA replication components is important to shape stem cell chromatin. Furthermore, manipulating one crucial DNA replication component can induce replication-coupled histone dynamics in nonstem cells to resemble those in stem cells.
干细胞表现出不对称的组蛋白遗传，而非干细胞祖细胞在雄性生殖系中呈现对称模式。在此，我们报告称，与后随链合成相关的组分，即DNA聚合酶α和δ，与祖细胞相比，在干细胞中的水平大幅降低，这促进了亲代组蛋白在复制叉处掺入的局部不对称性。通过基因手段削弱Polα会诱导祖细胞中局部复制偶联的组蛋白掺入模式类似于干细胞中的模式，这在核定位模式和染色质纤维中均可见。使用Polα抑制剂也以浓度依赖的方式重现了这一现象。在S期和M期，干细胞和祖细胞中局部新旧组蛋白的不对称性相当。总之，这些结果表明关键DNA复制组分的发育程序性表达对于塑造干细胞染色质很重要。此外，操纵一个关键的DNA复制组分可诱导非干细胞中复制偶联的组蛋白动态变化类似于干细胞中的变化。
