High-throughput functional testing of ENCODE segmentation predictions.
High-throughput functional testing of ENCODE segmentation predictions.
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DOI：
10.1101/gr.173518.114
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发表时间：
2014-10
期刊：
影响因子：
7
通讯作者：
Cohen BA
中科院分区：
文献类型：
--
作者：
Kwasnieski JC;Fiore C;Chaudhari HG;Cohen BA
基因组区域的组蛋白修饰状态被假设为反映了潜在基因组DNA的调节活性。基于这一假设，ENCODE项目联盟测量了几种细胞类型中基因组中多个组蛋白修饰的状态，并使用这些数据将基因组分割为具有不同预测调控活动的区域。我们在K562白血病细胞系中测量了2000多个这些预测的顺式调节活性。我们测试了K562细胞中被预测为增强子、弱增强子或抑制元件的基因组片段，以及其他被预测为H1人类胚胎干细胞系(H1-hESC)特异性增强子的序列。K562细胞中的增强子和弱增强子序列都比阴性对照更活跃，尽管令人惊讶的是，弱增强子片段比增强子片段驱动更高的表达。低水平的共价组蛋白修饰H3K36me3和H3K27ac被认为标志着活性增强子和转录的基因体，与更高的表达相关，并在一定程度上解释了弱增强子的活性高于增强子预测。虽然在我们的实验中，DNase I超敏反应(HS)是活性序列的一个很好的预测因子，但为了准确地识别高表达的序列，需要包括转录因子(TF)结合模型。总体而言，我们的结果表明，很大一部分ENCODE增强子预测(∼26%)具有调节活性，这表明组蛋白修饰状态可以反映基因组中序列的顺式调节活性，但特定的序列偏好，如TF结合位点，是顺式调节活性的因果决定因素。
The histone modification state of genomic regions is hypothesized to reflect the regulatory activity of the underlying genomic DNA. Based on this hypothesis, the ENCODE Project Consortium measured the status of multiple histone modifications across the genome in several cell types and used these data to segment the genome into regions with different predicted regulatory activities. We measured the cis-regulatory activity of more than 2000 of these predictions in the K562 leukemia cell line. We tested genomic segments predicted to be Enhancers, Weak Enhancers, or Repressed elements in K562 cells, along with other sequences predicted to be Enhancers specific to the H1 human embryonic stem cell line (H1-hESC). Both Enhancer and Weak Enhancer sequences in K562 cells were more active than negative controls, although surprisingly, Weak Enhancer segmentations drove expression higher than did Enhancer segmentations. Lower levels of the covalent histone modifications H3K36me3 and H3K27ac, thought to mark active enhancers and transcribed gene bodies, associate with higher expression and partly explain the higher activity of Weak Enhancers over Enhancer predictions. While DNase I hypersensitivity (HS) is a good predictor of active sequences in our assay, transcription factor (TF) binding models need to be included in order to accurately identify highly expressed sequences. Overall, our results show that a significant fraction (∼26%) of the ENCODE enhancer predictions have regulatory activity, suggesting that histone modification states can reflect the cis-regulatory activity of sequences in the genome, but that specific sequence preferences, such as TF-binding sites, are the causal determinants of cis-regulatory activity.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
9.8
作者：
ENCODE Project Consortium
通讯作者：
ENCODE Project Consortium
影响因子：
7
作者：
Gorkin DU;Lee D;Reed X;Fletez-Brant C;Bessling SL;Loftus SK;Beer MA;Pavan WJ;McCallion AS
通讯作者：
McCallion AS
影响因子：
4
作者：
Hess, J;Angel, P;Schorpp-Kistner, M
通讯作者：
Schorpp-Kistner, M
影响因子：
14.9
作者：
Flicek P;Ahmed I;Amode MR;Barrell D;Beal K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fairley S;Fitzgerald S;Gil L;García-Girón C;Gordon L;Hourlier T;Hunt S;Juettemann T;Kähäri AK;Keenan S;Komorowska M;Kulesha E;Longden I;Maurel T;McLaren WM;Muffato M;Nag R;Overduin B;Pignatelli M;Pritchard B;Pritchard E;Riat HS;Ritchie GR;Ruffier M;Schuster M;Sheppard D;Sobral D;Taylor K;Thormann A;Trevanion S;White S;Wilder SP;Aken BL;Birney E;Cunningham F;Dunham I;Harrow J;Herrero J;Hubbard TJ;Johnson N;Kinsella R;Parker A;Spudich G;Yates A;Zadissa A;Searle SM
通讯作者：
Searle SM