PRISM offers a comprehensive genomic approach to transcription factor function prediction

Abstract

The human genome encodes 1500-2000 different transcription factors (TFs). ChIP-seq is revealing the global binding profiles of a fraction of TFs in a fraction of their biological contexts. These data show that the majority of TFs bind directly next to a large number of context-relevant target genes, that most binding is distal, and that binding is context specific. Because of the effort and cost involved, ChIP-seq is seldom used in search of novel TF function. Such exploration is instead done using expression perturbation and genetic screens. Here we propose a comprehensive computational framework for transcription factor function prediction. We curate 332 high-quality nonredundant TF binding motifs that represent all major DNA binding domains, and improve cross-species conserved binding site prediction to obtain 3.3 million conserved, mostly distal, binding site predictions. We combine these with 2.4 million facts about all human and mouse gene functions, in a novel statistical framework, in search of enrichments of particular motifs next to groups of target genes of particular functions. Rigorous parameter tuning and a harsh null are used to minimize false positives. Our novel PRISM (predicting regulatory information from single motifs) approach obtains 2543 TF function predictions in a large variety of contexts, at a false discovery rate of 16%. The predictions are highly enriched for validated TF roles, and 45 of 67 (67%) tested binding site regions in five different contexts act as enhancers in functionally matched cells.

Comparative genomics as a tool to understand evolution and disease

“…As an example of this, the ENCODE Consortium annotated 80% of the human genome using a variety of overlapping experimental markers including transcription and histone modification (The ENCODE Project Consortium et al 2012); however, this catalog does not uniquely assign the function to specific bases but to an overall region of the genome. Thus, one should combine the functional signature of the cell type of interest with constraint patterns to delineate the specific function of constrained elements (The ENCODE Project Consortium et al 2007;Lindblad-Toh et al 2011;Wenger et al 2013). Figure 1.…”

Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements

“…We then searched for evolutionarily conserved matches to the structurally realistic motif arrangements using the PRISM phylogenetic footprinting method (see §4) [24]. We compared the number of matches in putative cis-regulatory DNA (conserved elements) with the number in genomic background DNA (unconserved elements that are at least 500 kb from known gene bodies and not in putative regulatory domains of genes annotated for TF and/or early developmental activity as defined by GREAT [25]), and identified arrangements enriched in conserved regions (binomial test).…”

“…For example, our predictions may be fed to PRISM to infer TF complex functions [24]. Predictions of our 422 TF complexes, their motifs, potential TF partners and genomic binding sites are publicly accessible at http://bejerano.stanford.edu/complex.…”

“…The resource provides access to the predicted TF complex motifs, their FDRs and suggestions of potential TF partners and binding sites, which can be easily assessed for gene targets and functional enrichment computed via the PRISM framework (see electronic supplementary material, figure S7) [24,25]. We hope that the predictions available in this resource will accelerate future structural and genomic studies of TF cooperativity.…”

“…For each pair of 3DPWMs, we identified conserved binding sites using PRISM [24] in all sequences in the set of CNEs. For each pair of 3DPWMs, we analysed the overlapping region (corresponding to the length of the two 3DPWMs) and 0-25 bases up and downstream of the overlapping region for both relative orientations.…”