Sequence signatures extracted from proximal promoters can be used to predict distal enhancers

Abstract

BackgroundGene expression is controlled by proximal promoters and distal regulatory elements such as enhancers. While the activity of some promoters can be invariant across tissues, enhancers tend to be highly tissue-specific.ResultsWe compiled sets of tissue-specific promoters based on gene expression profiles of 79 human tissues and cell types. Putative transcription factor binding sites within each set of sequences were used to train a support vector machine classifier capable of distinguishing tissue-specific promoters from control sequences. We obtained reliable classifiers for 92% of the tissues, with an area under the receiver operating characteristic curve between 60% (for subthalamic nucleus promoters) and 98% (for heart promoters). We next used these classifiers to identify tissue-specific enhancers, scanning distal non-coding sequences in the loci of the 200 most highly and lowly expressed genes. Thirty percent of reliable classifiers produced consistent enhancer predictions, with significantly higher densities in the loci of the most highly expressed compared to lowly expressed genes. Liver enhancer predictions were assessed in vivo using the hydrodynamic tail vein injection assay. Fifty-eight percent of the predictions yielded significant enhancer activity in the mouse liver, whereas a control set of five sequences was completely negative.ConclusionsWe conclude that promoters of tissue-specific genes often contain unambiguous tissue-specific signatures that can be learned and used for the de novo prediction of enhancers.

Identification of a functional enhancer variant within the chronic pancreatitis‐associatedSPINK1c.101A>G (p.Asn34Ser)‐containing haplotype

“…The remaining single variant, rs142703147C>A (c.-4141T), is located approximately 4 kb from the SPINK1 promoter, consistent with the current consensus that enhancers tend to be located within 10 kb of their associated transcription start sites genome wide (MacIsaac et al, 2010;Taher et al, 2013). The functionality of this variant was strongly supported by evolutionary conservation and chromatin accessibility data (Fig.…”

“…There is increasing evidence that the spatial and temporal expression of genes is enabled by the coordinated action of multiple transcription factors through CRMs (Lelli, Slattery, & Mann, 2012). Moreover, distal CRMs, also called enhancers, can often be predicted by sequence signatures extracted from proximal promoters (Taher, Smith, Kim, Ahituv, & Ovcharenko, 2013). Given the important roles played by HNF1A and PTF1L in adult pancreatic acinar cells (Holmstrom et al, 2011;Masui et al, 2008;Molero et al, 2012), it did not appear unreasonable to speculate that their closely spaced TFBSs within the SPINK1 proximal promoter ( Fig.…”

Novel principles of gamma-retroviral insertional transcription activation in murine leukemia virus-induced end-stage tumors

“…While promoters and promoter-proximal enhancers are functionally similar [31,32], promoter-distal enhancers may enhance transcription from thousands of bp away. One example is the distal limb bud enhancer of mouse Shh which is positioned 1 Mb from the Shh promoter [33,34].…”

In silico identification of enhancers on the basis of a combination of transcription factor binding motif occurrences

“…have built a model to predict active enhancers on the basis of histone modifications and collective motif data. Taher et al 23. have developed a model to predict distal enhancers by using the sequence signatures of promoters and the Support Vector Machine (SVM) algorithm.…”