Dynamically reorganized chromatin is the key for the reprogramming of somatic cells to pluripotent cells.
Dynamically reorganized chromatin is the key for the reprogramming of somatic cells to pluripotent cells.
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动态重组的染色质是体细胞重编程为多能细胞的关键
DOI：
10.1038/srep17691
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发表时间：
2015-12-07
影响因子：
4.6
通讯作者：
Yao H
中科院分区：
文献类型：
--
作者：
Huang K;Zhang X;Shi J;Yao M;Lin J;Li J;Liu H;Li H;Shi G;Wang Z;Zhang B;Chen J;Pan G;Jiang C;Pei D;Yao H
核小体定位和组蛋白修饰在基因调控中起关键作用，但它们在重编程中的作用尚未完全阐明。在这里，我们确定了小鼠胚胎成纤维细胞（MEF）、诱导多能干细胞（iPSC）和前iPSC中的全基因组核小体覆盖率和组蛋白甲基化占用率。我们发现，在前iPSC中，核小体占据在启动子区域增加，在基因间区域减少，然后在iPSC中恢复到中等水平。我们还发现，前iPSC中的核小体比MEF和iPSC中的核小体更具阶段性。在重编程过程中，核小体重组和转录起始位点（TSS）周围的组蛋白甲基化与特异的转录活性高度协调。二价启动子逐渐增加，而抑制性启动子逐渐减少。活性基因的高CpG（HCG）启动子的特征在于TSS处的核小体耗尽，而低CpG（LCG）启动子表现出相反的特征。此外，我们发现，维生素C（VC）在从pre-iPSC向iPSC过渡期间促进特定基因上典型的H3 K4 me 3和H3 K27 me 3修饰的核小体的重组。这些数据表明，前iPSC具有比MEF和iPSC更开放和定相的染色质结构。最后，本研究揭示了核小体定位和染色质组织在重编程过程中基因调控的动态和关键作用。
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.