A system for genome-wide histone variant dynamics in ES cells reveals dynamic MacroH2A2 replacement at promoters.
A system for genome-wide histone variant dynamics in ES cells reveals dynamic MacroH2A2 replacement at promoters.
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DOI：
10.1371/journal.pgen.1004515
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发表时间：
2014-08
期刊：
影响因子：
4.5
通讯作者：
Rando OJ
中科院分区：
文献类型：
--
作者：
Yildirim O;Hung JH;Cedeno RJ;Weng Z;Lengner CJ;Rando OJ
体内核小体子集的动态交换在染色质状态的表观遗传、染色质绝缘体功能、染色体折叠和胚胎干细胞多能状态的维持中发挥重要作用。在这里，我们将脉冲追踪策略扩展到小鼠胚胎干细胞和体细胞组织中的几种组蛋白变体，以对组蛋白动力学进行全基因组测量，概括了充分表征的 H3.3 组蛋白变体的预期特征。我们将该系统扩展到研究较少的 MacroH2A2 变体，通常被描述为“抑制性”组蛋白变体，其在染色质中的积累被认为可以修复分化细胞的表观遗传状态。出乎意料的是，我们发现虽然 MacroH2A2 的大基因间块与基因组稳定相关，但 MacroH2A2 的启动子相关峰在 ES 细胞中表现出相对快速的交换动态，特别是在高度转录的基因上。在分化为胚胎成纤维细胞后，MacroH2A2 主要在基因贫乏区域的额外长、稳定相关的块中获得，而启动子的整体更新则大大抑制。我们的结果揭示了 MacroH2A2 变体在多能细胞中意想不到的动态行为，并为未来体内组织特异性组蛋白动力学研究提供了资源。细胞记住正确细胞命运的能力至少部分取决于基因组的包装方式。胚胎干 (ES) 细胞能够转变为体内的任何细胞类型，是一个经过充分研究的系统，用于了解基因组包装（染色质）如何控制细胞状态。 ES 细胞染色质更令人好奇的方面之一是其“超动态”性质，因为据报道，构成染色质的组蛋白在这些细胞中的 DNA 上和脱下时会快速交换。在这里，我们报告了一种用于研究小鼠 ES 细胞中组蛋白动力学的脉冲追踪系统，并报告了两种组蛋白变体 H3.3 和 MacroH2A2 的动力学。值得注意的是，MacroH2A2 在 ES 细胞中具有高度动态性，基因启动子上发生快速交换，同时具有覆盖大块基因组的更稳定的结合结构域。分化为成纤维细胞后，MacroH2A2 与基因组的结合变得更加稳定，这与该组蛋白变体在“锁定”基因组抑制区域中发挥作用的观点一致。这些结果为组蛋白动力学在控制细胞状态遗传中的关键作用提供了进一步的证据。
Dynamic exchange of a subset of nucleosomes in vivo plays important roles in epigenetic inheritance of chromatin states, chromatin insulator function, chromosome folding, and the maintenance of the pluripotent state of embryonic stem cells. Here, we extend a pulse-chase strategy for carrying out genome-wide measurements of histone dynamics to several histone variants in murine embryonic stem cells and somatic tissues, recapitulating expected characteristics of the well characterized H3.3 histone variant. We extended this system to the less-studied MacroH2A2 variant, commonly described as a “repressive” histone variant whose accumulation in chromatin is thought to fix the epigenetic state of differentiated cells. Unexpectedly, we found that while large intergenic blocks of MacroH2A2 were stably associated with the genome, promoter-associated peaks of MacroH2A2 exhibited relatively rapid exchange dynamics in ES cells, particularly at highly-transcribed genes. Upon differentiation to embryonic fibroblasts, MacroH2A2 was gained primarily in additional long, stably associated blocks across gene-poor regions, while overall turnover at promoters was greatly dampened. Our results reveal unanticipated dynamic behavior of the MacroH2A2 variant in pluripotent cells, and provide a resource for future studies of tissue-specific histone dynamics in vivo. The ability of cells to remember the correct cell fate is at least partly dependent on how the genome is packaged. Embryonic stem (ES) cells, which have the ability to become any cell type in the body, are a particularly well-studied system for understanding how the packaging of the genome – chromatin – controls cell state. One of the more curious aspects of ES cell chromatin is its “hyperdynamic” nature, as the histone proteins that comprise chromatin have been reported to exchange rapidly on and off the DNA in these cells. Here, we report a pulse chase system for studying histone dynamics in mouse ES cells, and report on the dynamics of two histone variants, H3.3 and MacroH2A2. Notably, MacroH2A2 is highly dynamic in ES cells, with rapid exchange occurring over gene promoters, alongside much more stably-bound domains that cover large blocks of the genome. Upon differentiation to fibroblasts MacroH2A2 becomes much more stably-bound to the genome, consistent with the idea that this histone variant plays a role in “locking down” repressed regions the genome. These results provide further evidence for a key role of histone dynamics in control of cell state inheritance.
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影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
DOI：
10.1073/pnas.172403699
发表时间：
2002-12-10
影响因子：
11.1
作者：
Ahmad, K;Henikoff, S
通讯作者：
Henikoff, S
影响因子：
10.5
作者：
Gamble, Matthew J.;Frizzell, Kristine M.;Kraus, W. Lee
通讯作者：
Kraus, W. Lee
DOI：
10.1084/jem.20101438
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Christophersen NS;Helin K
通讯作者：
Helin K
影响因子：
16
作者：
Jamai, Adil;Imoberdorf, Rachel Maria;Strubin, Michel
通讯作者：
Strubin, Michel