The functional consequences of variation in transcription factor binding.
The functional consequences of variation in transcription factor binding.
复制标题
转录因子结合变异的功能后果。
DOI：
10.1371/journal.pgen.1004226
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发表时间：
2014-03
期刊：
影响因子：
4.5
通讯作者：
Gilad Y
中科院分区：
文献类型：
--
作者：
Cusanovich DA;Pavlovic B;Pritchard JK;Gilad Y
人类遗传学的一个目标是了解精确和动态基因表达程序的信息如何在基因组中编码。转录因子（TF）与DNA调控元件的相互作用在决定基因表达输出中显然起着重要作用，但对功能性转录因子结合的调控逻辑知之甚少。许多研究都集中在表征TF结合的基因组位置，但目前还不清楚在何种程度上TF结合在任何特定的基因座有功能的后果，基因表达输出。为了评估功能性TF结合的背景，我们在一个HapMap淋巴母细胞系中敲低了59个TF和染色质修饰剂。然后，我们确定了基因的表达受到敲除的影响。我们将基因表达数据与表达基因的转录起始位点的10 kb内的转录因子结合数据（基于ChIP-seq和DNase-seq）进行比对。这种数据组合使我们能够推断功能性TF结合。使用这种方法，我们发现，只有一小部分基因的结合因子的差异表达后，该因子的敲低，这表明TF和染色质之间的相互作用不会导致可测量的变化，在基因表达水平的推定的靶基因。我们发现，功能性TF结合富集在含有大量TF结合位点的调控元件中，在具有预测的更高结合亲和力的位点处，以及在被注释为“活性增强子”的基因组区域中富集的位点处。基因组学中的一个重要问题是了解一类称为“转录因子”的蛋白质如何以细胞类型特异性方式控制基因组中其他基因的表达水平--这一过程对人类发育至关重要。解决这个问题的一个主要方法是研究这些转录因子在基因组中的结合位置，但这并不能告诉我们这种结合对基因表达水平的影响，而且人们普遍认为，大部分结合并不会强烈影响基因表达。为了解决这个问题，我们人工降低了细胞中59种不同转录因子的浓度，然后检查哪些基因受到转录因子水平降低的影响。我们的研究结果暗示了一些可能影响结合功能的属性，但它们也表明功能与非功能结合的简单模型可能是不够的。
One goal of human genetics is to understand how the information for precise and dynamic gene expression programs is encoded in the genome. The interactions of transcription factors (TFs) with DNA regulatory elements clearly play an important role in determining gene expression outputs, yet the regulatory logic underlying functional transcription factor binding is poorly understood. Many studies have focused on characterizing the genomic locations of TF binding, yet it is unclear to what extent TF binding at any specific locus has functional consequences with respect to gene expression output. To evaluate the context of functional TF binding we knocked down 59 TFs and chromatin modifiers in one HapMap lymphoblastoid cell line. We then identified genes whose expression was affected by the knockdowns. We intersected the gene expression data with transcription factor binding data (based on ChIP-seq and DNase-seq) within 10 kb of the transcription start sites of expressed genes. This combination of data allowed us to infer functional TF binding. Using this approach, we found that only a small subset of genes bound by a factor were differentially expressed following the knockdown of that factor, suggesting that most interactions between TF and chromatin do not result in measurable changes in gene expression levels of putative target genes. We found that functional TF binding is enriched in regulatory elements that harbor a large number of TF binding sites, at sites with predicted higher binding affinity, and at sites that are enriched in genomic regions annotated as “active enhancers.” An important question in genomics is to understand how a class of proteins called “transcription factors” controls the expression level of other genes in the genome in a cell-type-specific manner – a process that is essential to human development. One major approach to this problem is to study where these transcription factors bind in the genome, but this does not tell us about the effect of that binding on gene expression levels and it is generally accepted that much of the binding does not strongly influence gene expression. To address this issue, we artificially reduced the concentration of 59 different transcription factors in the cell and then examined which genes were impacted by the reduced transcription factor level. Our results implicate some attributes that might influence what binding is functional, but they also suggest that a simple model of functional vs. non-functional binding may not suffice.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
3.7
作者：
de Candia P;Blekhman R;Chabot AE;Oshlack A;Gilad Y
通讯作者：
Gilad Y
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：
2.1
作者：
Gagnon-Bartsch, Johann A.;Speed, Terence P.
通讯作者：
Speed, Terence P.
影响因子：
4.5
作者：
Aleman, Lourdes M.;Doench, John;Sharp, Phillip A.
通讯作者：
Sharp, Phillip A.