Mapping dynamic histone acetylation patterns to gene expression in nanog-depleted murine embryonic stem cells.
Mapping dynamic histone acetylation patterns to gene expression in nanog-depleted murine embryonic stem cells.
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DOI：
10.1371/journal.pcbi.1001034
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发表时间：
2010-12-16
影响因子：
4.3
通讯作者：
Troyanskaya OG
中科院分区：
文献类型：
--
作者：
Markowetz F;Mulder KW;Airoldi EM;Lemischka IR;Troyanskaya OG
胚胎干细胞（ESC）具有无限自我更新和分化成三个胚层中任何一个的潜力。人们对自我更新、多能性维持和谱系规范的分子机制知之甚少，但最近的结果指出表观遗传机制的关键作用。在本研究中，我们重点量化组蛋白 3 乙酰化 (H3K9,14ac) 对小鼠胚胎干细胞基因表达的影响。我们分析了通过沉默 Nanog（ESC 调节中的关键转录因子）引发的细胞分化的前五天测量的全基因组组蛋白乙酰化模式和基因表达谱。我们使用监督和无监督统计模型探索组蛋白乙酰化数据的时间和空间动态及其与基因表达的相关性。在全基因组范围内，乙酰化的变化与 mRNA 表达的变化显着相关，令人惊讶的是，这种一致性随着时间的推移而增加。我们在平衡交叉验证程序中量化了组蛋白乙酰化对基因表达变化的预测能力。在一项深入研究中，我们重点关注小鼠 ESC 调控网络的核心基因，包括在最近的全基因组 RNAi 筛选和 PluriNet（计算衍生的干细胞特征）中发现的基因。我们发现，与基因组的其余部分相比，ESC 特异性基因随着时间的推移表现出明显更多的乙酰化信号和更强的乙酰化下降，这通常不会反映在一致的表达变化中。这些结果揭示了组蛋白乙酰化与基因表达之间关系的复杂性，并且是剖析决定干细胞命运的多层调控机制的一步。干细胞分化和自我更新的维持本质上是复杂的过程，需要在许多不同的细胞水平上进行协调调节。在这里，我们重点关注两个重要层之间的关系，并在分化的前五天中跟踪它。第一层——通过一个组蛋白的乙酰化来测量——描述了 DNA 的哪些部分被紧紧包裹，哪些部分是开放的。第二层描述了通过 mRNA 表达测量的基因活性。使用多种统计方法，我们表明组蛋白乙酰化的变化对于基因表达具有很强的预测性，并且两个水平之间的一致性随着时间的推移而增加。专注于胚胎干细胞调控网络的核心基因，我们发现关键基因在开始时表现出非常高的乙酰化信号，但随着时间的推移迅速降低，表明它们位于最初开放的区域，但随后迅速关闭。这些结果是更好地理解组蛋白乙酰化与基因表达之间关系的复杂性的一步，这将有助于剖析决定干细胞命运的多层调控机制。
Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in a concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step forward to dissect the multilayer regulatory mechanisms that determine stem cell fate. Stem cell differentiation and the maintenance of self-renewal are intrinsically complex processes that require coordinated regulation on many different cellular levels. Here we focus on the relationship between two important layers and follow it over the first five days of differentiation. The first layer – measured by acetylation of one of the histone proteins – describes which parts of the DNA are tightly wrapped up and which lie open. The second layer describes the activity of genes measured by their mRNA expression. Using a wide array of statistical approaches we show that changes in histone acetylation are very predictive for gene expression and that the concordance between the two levels increases over time. Concentrating on genes central to the regulatory networks in embryonic stem cells we find that key genes show very high acetylation signal in the beginning that decreases quickly over time, indicating that they lie in initially open regions that are rapidly closing down. These results are a step forward to a better understanding of the complexities of the relationship between histone acetylation and gene expression, which will help to dissect the multilayer regulatory mechanisms that determine stem cell fate.
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影响因子：
4.3
作者：
Airoldi EM
通讯作者：
Airoldi EM
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
DOI：
10.1073/pnas.51.5.786
发表时间：
1964-01-01
影响因子：
11.1
作者：
ALLFREY, VG;FAULKNER, R;MIRSKY, AE
通讯作者：
MIRSKY, AE