Detection of new pioneer transcription factors as cell-type-specific nucleosome binders

Abstract

Wrapping of DNA into nucleosomes restricts DNA accessibility and the recognition of binding motifs by transcription factors. A certain class of transcription factors, so-called pioneer transcription factors, can specifically recognize their binding sites on nucleosomal DNA, initiate local chromatin opening and facilitate the binding of co-factors in a cell-type-specific manner. For the vast majority of human pioneer transcription factors, the locations of their binding sites, mechanisms of binding and regulation remain unknown. We have developed a computational method to predict the cell-type-specific ability of transcription factors to bind nucleosomes by integrating ChIP-seq, MNaseq-seq and DNase-seq data with the details of nucleosome structure. We have achieved classification accuracy with AUC=0.94 in discriminating pioneer factors from canonical transcription factors and predicted 32 potential pioneer transcription factors as nucleosome binders in embryonic cell differentiation. Lastly, we systemically analyzed the interaction modes between various pioneer factors and detected several clusters of distinctive binding sites on nucleosomal DNA.

Mechanistic basis of gene regulation by SRCAP and H2A.Z

“…As pTFs are characterized by their ability to bind nucleosomal DNA, we reasoned that their binding might be particularly sensitive to nucleosome composition. We thus quantified the number of pTFs that were enriched in the up vs downregulated motifs, using a classification of pTFs based on 57,58 (see Methods). We found that 87 out of the 376 up-TFs (23.1%) but only 7 out of the 97 (7.2%) down-TFs after 4 h of IAA treatment were known pTFs (Figure S5E).…”

“…The list of pioneer transcription factors (pTFs) (Table S5) was compiled from the list published by Lemma et al 57 in their supplementary Table 4 and Peng et al 58 in their supplementary Table 5 and 6.…”