Contributed
DNA sequence repeat symmetry determines transcription factor binding in embryonic stem cells

Highly complex and dynamic transcription factor (TF)-DNA binding network maintains the genome-wide transcriptional program in any cell. It is commonly assumed that specific transcription factor (TF)-DNA binding recognition based on the presence of short, specific motifs represents the only mechanism providing genome-wide TF-DNA binding specificity. Contrary to such assumption, I will show in my talk that despite the enormous sequence complexity of the TF-DNA binding landscape in differentiating human embryonic stem cells, this landscape can be quantitatively characterized in simple terms, using the notion of DNA sequence repeat symmetry. It is currently recognized that specific TF binding sites provide only a limited understanding of the global TF-DNA binding map, and the genome context significantly influences, and in many cases dominates TF-DNA binding preferences. Here, I will discuss design principles of TF recognition by genomic DNA in differentiating human embryonic stem cells for tens of TFs and five histone modifications in four developmental layers. This analysis reveals that DNA sequence repeat symmetry plays a central role in defining TF-DNA binding preferences across different developmental layers. In particular, we find that different TFs bind similar symmetry patterns within a given developmental layer. Upon transitions between different developmental layers, most TFs possess dominant preferences for similar DNA repeat symmetry types. Histone modifications also exhibit strong preferences for similar DNA repeat symmetry patterns, with the symmetry strength differentiating between different histone modifications. Overall, our findings show that despite the enormous sequence complexity of the TF-DNA binding landscape in human embryonic stem cells, this landscape can be quantitatively characterized in simple terms, using the notion of DNA sequence repeat symmetry. We expect that the mechanistic understanding of TF recognition by DNA enriched in repetitive sequence elements will be relevant for any biological or synthetic system involving TFs and DNA.