12月7日，Scientific Reports在线发表了中国科学院广州生物医药与健康研究院姚红杰课题组与同济大学教授江赐忠课题组相关人员的合作研究成果Dynamically reorganized chromatin is the key for the reprogramming of somatic cells to pluripotent cells。

2006年，日本科学家Yamanaka成功利用四个转录因子Oct4、Sox2、Klf4和c-Myc将小鼠胚胎成纤维细胞诱导成多能性干细胞（ipSC）。在MEF细胞重编程为ipS细胞的过程中，细胞内的表观遗传信息发生巨大的变化。核小体作为染色质的基本功能单位，主要由组蛋白八聚体及缠绕在组蛋白八聚体上的146 bp的核心DNA序列组成。组蛋白上能发生关键的表观遗传修饰（如甲基化、乙酰化和泛素化等），进而调控特定基因的表达。以往的研究描绘了线虫、人等全基因组范围内的核小体定位图谱，然而，对于体细胞重编程过程中核小体的动态变化及对基因表达调控的影响的报道还较少。

姚红杰课题组与江赐忠课题组合作，利用MEFs、pre-ipSCs和ipSCs三个阶段的细胞作为研究模型，系统地描绘重编程过程中核小体定位及组蛋白修饰的动态变化及对基因表达的影响。该研究成果发现在体细胞重编程过程中，pre-ipS细胞的染色质最为开放，其开放程度为pre-ipSCs>ipSCs>MEFs。全基因组范围内核小体定位的情况为：pre-ipS细胞的核小体fuzziness最小，为26 bp；MEF细胞（31 bp）和ipS细胞（32 bp）的核小体fuzziness分布相近。在重编程过程中，不同组蛋白甲基化修饰（H3K4me3/H3K27me3/H3K9me3）在基因的启动子区发生明显有规律的动态变化，而这种变化和基因的表达水平密切相关。最后，在pre-ipS细胞转化为ipS细胞的过程中，维生素C能够显著影响核小体及组蛋白甲基化修饰（H3K4me3/H3K27me3）在重编程相关基因启动子区的重定位。

相关成果得到国家自然科学基金委、科技部、中国科学院、广东省、广州市科技项目的资助。

原文摘要：

Dynamically reorganized chromatin is the key for the reprogramming of somatic cells to pluripotent cells

Nucleosome positioning and histone modification play a critical role in gene regulation, but their role during reprogramming has not been fully elucidated. Here, we determined the genome-wide nucleosome coverage and histone methylation occupancy in mouse embryonic fibroblasts (MEFs), induced pluripotent stem cells (ipSCs) and pre-ipSCs. We found that nucleosome occupancy increases in promoter regions and decreases in intergenic regions in pre-ipSCs, then recovers to an intermediate level in ipSCs. We also found that nucleosomes in pre-ipSCs are much more phased than those in MEFs and ipSCs. During reprogramming, nucleosome reorganization and histone methylation around transcription start sites (TSSs) are highly coordinated with distinctively transcriptional activities. Bivalent promoters gradually increase, while repressive promoters gradually decrease. High CpG (HCG) promoters of active genes are characterized by nucleosome depletion at TSSs, while low CpG (LCG) promoters exhibit the opposite characteristics. In addition, we show that vitamin C (VC) promotes reorganizations of canonical, H3K4me3- and H3K27me3-modified nucleosomes on specific genes during transition from pre-ipSCs to ipSCs. These data demonstrate that pre-ipSCs have a more open and phased chromatin architecture than that of MEFs and ipSCs. Finally, this study reveals the dynamics and critical roles of nucleosome positioning and chromatin organization in gene regulation during reprogramming.