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.

Deciphering principles of nucleosome interactions and impact of cancer-associated mutations from comprehensive interaction network analysis

“…Such preferences on the DNA binding sites may be related to histone tail interactions [ 8 , 42 ]. Our results have further unraveled diverse binding modes between pioneer factors and nucleosome structures and this is supported by recent experimental and computational studies [ 44 , 55–57 ].…”

“…Although pioneer factors have been previously suggested to mainly target entry/exit of nucleosomal DNA, we show that pioneer factors can have different binding modes with nucleosome structures and indeed target multiple DNA regions such as SHL ±2, ±5, ±6 and linker DNA ( Supplementary Figure 17 ). This is also supported by our recent large-scale analysis of nucleosome-pioneer factor binding profiles using ChiP-seq and MNase-seq data [ 44 ].…”

“…Pioneer factors are critical nucleosome binders and specifically recognize nucleosomal DNA to induce the chromatin opening [ 7 , 43 , 44 ]. Here, we have further analyzed the binding modes of several known pioneer factors with nucleosome including SOX2, SOX11, OCT4, CBF1 and P53.…”

Identification of mammalian transcription factors that bind to inaccessible chromatin

“…Here, we find a higher proportion of TFs that bind chromatin independent of the DNA accessibility status (approximately one third). Furthermore, another recent large scale study identified 32 TFs as potential pioneer TFs in several human cell lines ( 66 ). Most importantly, 15 (out of 33) of the TFs that we classify as AIFs (ATF1, BACH1, CREB1, CTCF, CUX1, E2F6, USF2, EGR1, ELK1, GABPA, NFYA, NFYB, USF1, USF2 and ZKSCAN1) and 13 (out of 49) that we classify as partial AIFs (ATF1, CEBPB, E2F1, CUX1, NR4A1, ETS1, HMBOX1, MAX, NFATC3, NR2F2, POU5F1, SP1 and SREBF1) in this study were previously identified as potential pioneer TFs using different methods in ( 42 , 66 ).…”

“…Furthermore, another recent large scale study identified 32 TFs as potential pioneer TFs in several human cell lines ( 66 ). Most importantly, 15 (out of 33) of the TFs that we classify as AIFs (ATF1, BACH1, CREB1, CTCF, CUX1, E2F6, USF2, EGR1, ELK1, GABPA, NFYA, NFYB, USF1, USF2 and ZKSCAN1) and 13 (out of 49) that we classify as partial AIFs (ATF1, CEBPB, E2F1, CUX1, NR4A1, ETS1, HMBOX1, MAX, NFATC3, NR2F2, POU5F1, SP1 and SREBF1) in this study were previously identified as potential pioneer TFs using different methods in ( 42 , 66 ). In addition to pioneers, AIFs also include bookmarking TFs (binding both open and dense chromatin) and co-factors of pioneers (being recruited by pioneer factors), which indicates that our estimates of the number of TFs that bind in an accessibility independent fashion are supported by this previous study.…”