Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.
Regenerative Biosciences Center (RBC), University of Georgia, Athens, GA, USA.
Commun Biol. 2023 Dec 12;6(1):1258. doi: 10.1038/s42003-023-05641-0.
The mechanisms leading to changes in mesoscale chromatin organization during cellular aging are unknown. Here, we used transcriptional activator-like effectors, RNA-seq and superresolution analysis to determine the effects of genotoxic stress on oocyte chromatin structure. Major satellites are organized into tightly packed globular structures that coalesce into chromocenters and dynamically associate with the nucleolus. Acute irradiation significantly enhanced chromocenter mobility in transcriptionally inactive oocytes. In transcriptionally active oocytes, irradiation induced a striking unfolding of satellite chromatin fibers and enhanced the expression of transcripts required for protection from oxidative stress (Fermt1, Smg1), recovery from DNA damage (Tlk2, Rad54l) and regulation of heterochromatin assembly (Zfp296, Ski-oncogene). Non-irradiated, senescent oocytes exhibit not only high chromocenter mobility and satellite distension but also a high frequency of extra chromosomal satellite DNA. Notably, analysis of biological aging using an oocyte-specific RNA clock revealed cellular communication, posttranslational protein modifications, chromatin and histone dynamics as the top cellular processes that are dysregulated in both senescent and irradiated oocytes. Our results indicate that unfolding of heterochromatin fibers following acute genotoxic stress or cellular aging induced the formation of distended satellites and that abnormal chromatin structure together with increased chromocenter mobility leads to chromosome instability in senescent oocytes.
导致细胞衰老过程中中等尺度染色质组织变化的机制尚不清楚。在这里，我们使用转录激活子样效应物、RNA-seq 和超分辨率分析来确定遗传毒性应激对卵母细胞染色质结构的影响。主要卫星被组织成紧密堆积的球状结构，这些结构融合成染色中心，并与核仁动态相关联。急性辐照显著增强了转录不活跃卵母细胞中的染色中心迁移。在转录活跃的卵母细胞中，辐照诱导卫星染色质纤维明显展开，并增强了对氧化应激（Fermt1、Smg1）、DNA 损伤修复（Tlk2、Rad54l）和异染色质组装调控（Zfp296、Ski-oncogene）所需转录本的表达。未经辐照的衰老卵母细胞不仅表现出高染色中心迁移率和卫星膨胀，而且还具有高频率的染色体外卫星 DNA。值得注意的是，使用卵母细胞特异性 RNA 时钟分析生物衰老表明，细胞间通讯、翻译后蛋白质修饰、染色质和组蛋白动力学是衰老和辐照卵母细胞中失调的顶级细胞过程。我们的结果表明，急性遗传毒性应激或细胞衰老后异染色质纤维的展开导致膨胀的卫星的形成，异常的染色质结构加上染色中心迁移率的增加导致衰老卵母细胞中的染色体不稳定性。
