Cell Type Specific DNA Signatures of Transcription Factor Binding

Transcription factors (TFs) bind to different parts of the genome in different types of cells. These differences may be due to alterations in the DNA-binding preferences of a TF itself, or mechanisms such as chromatin accessibility, steric hindrance, or competitive binding, that result in a DNA "signature" of differential binding. We propose a method called SigTFB (Signatures of TF Binding), based on deep learning, to detect and quantify cell type specificity in a TFs DNA-binding signature. We conduct a wide scale investigation of 194 distinct TFs across various cell types. We demonstrate the existence of cell type specificity in approximately 30% of the TFs. We stratify our analysis by different antibodies for the same TF, to rule out the possibility of certain technical artifacts, yet we find that cell type specificity estimates are largely consistent when the same TF is assayed with different antibodies. To further explain the biology behind a TFs cell type specificity, or lack thereof, we conduct a wide scale motif enrichment analysis of all TFs in question. We show that the presence of alternate motifs correlates with a higher degree of cell type specificity in TFs, such as ATF7, while finding consistent motifs throughout is usually associated with the absence of cell type specificity in a TF, such as CTCF. In particular, we observe that several important TFs show distinct DNA binding signatures in different cancer cell types, which may point to important differences in modes of action. Moreover, we find that motif enrichment sometimes correlates with gene expression in TFs with higher cell type specificity. Our comprehensive investigation provides a basis for further study of the mechanisms behind differences in TF-DNA binding in different cell types.