Comprehensive prediction in 78 human cell lines reveals rigidity and compactness of transcription factor dimers

Abstract

The binding of transcription factors (TFs) to their specific motifs in genomic regulatory regions is commonly studied in isolation. However, in order to elucidate the mechanisms of transcriptional regulation, it is essential to determine which TFs bind DNA cooperatively as dimers and to infer the precise nature of these interactions. So far, only a small number of such dimeric complexes are known. Here, we present an algorithm for predicting cell-type-specific TF-TF dimerization on DNA on a large scale, using DNase I hypersensitivity data from 78 human cell lines. We represented the universe of possible TF complexes by their corresponding motif complexes, and analyzed their occurrence at cell-type-specific DNase I hypersensitive sites. Based on~1.4 billion tests for motif complex enrichment, we predicted 603 highly significant celltype-specific TF dimers, the vast majority of which are novel. Our predictions included 76% (19/25) of the known dimeric complexes and showed significant overlap with an experimental database of protein-protein interactions. They were also independently supported by evolutionary conservation, as well as quantitative variation in DNase I digestion patterns. Notably, the known and predicted TF dimers were almost always highly compact and rigidly spaced, suggesting that TFs dimerize in close proximity to their partners, which results in strict constraints on the structure of the DNA-bound complex. Overall, our results indicate that chromatin openness profiles are highly predictive of cell-type-specific TF-TF interactions. Moreover, cooperative TF dimerization seems to be a widespread phenomenon, with multiple TF complexes predicted in most cell types.

ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors

“…6D). This motif, which resembles a FOXA1 motif described in another study (Jankowski et al 2013), aligns with the FOXA1 motif in both forward and reverse orientation, and the footprint profile for this palindromic sequence can be explained by FOXA1 binding in two orientations (Fig. 6D).…”

“…Structural alignment of the homologous FOXK1 protein indicated that this motif can be simultaneously bound by two FOX proteins ( Fig. 6D; Jankowski et al 2013). However, since the footprint is derived from many cells, it might also reflect FOXA1 binding in one orientation for some cells and in the opposite orientation for others.…”

Base-resolution models of transcription factor binding reveal soft motif syntax

“…This is consistent with previous observations that retrotransposons may contain multiple ancestral TF binding sites [88][89][90][91][92] ( Figure S14A). Among all motif pairs, the top 1% most frequent distances mapped in 83% to ERVs and were often larger than 20 bp (Figure S14B,C), which exceeds the typical distance between motifs found in composite motifs that promote TF cooperativity 93,94 . This suggests that over-represented strict motif spacings alone are not a reliable indicator for functional motif syntax.…”

Synergetic regulatory networks mediated by oncogene-driven microRNAs and transcription factors in serous ovarian cancer

“…There are FFLs with two TFs found by experimental work 61 and theoretical analyses 34, 62 . In addition to TF-TF FFLs, two TF regulators may form regulatory TF dimers 63 or more complex regulatory units to affect the downstream gene expression 64 .…”