סמינר לפיזיקה של מערכות ביולוגיות וחומרים רכים: Design Principles of Protein-DNA Recognition Specificity in Embryonic Stem Cells

Abstract:

Transcription factors (TFs) bind genomic DNA regulating gene expression and developmental programs in embryonic stem cells (ESCs). Even though comprehensive genome-wide molecular maps for TF-DNA binding are experimentally available for key pluripotency-associated TFs, the understanding of molecular design principles responsible for TF-DNA recognition remains incomplete. In this talk, I will show that binding preferences of key pluripotency TFs exhibit bimodality in the local GC-content distribution. Sequence-dependent binding specificity of these TFs is distributed across three major contributions. First, local GC-content is dominant in high-GC-content regions. Second, recognition of specific k-mers is predominant in low-GC-content regions. Third, short tandem repeats (STRs) are highly predictive in both low- and high-GC-content regions. In sharp contrast, binding preferences of a key oncogenic protein, c-Myc, are exclusively dominated by local GC-content and STRs in high-GC-content genomic regions. I will propose that the transition in the TF-DNA binding landscape upon ESC differentiation is solely regulated by the concentration of c-Myc, which forms a bivalent c-Myc-Max heterotetramer upon promoter binding by looping DNA, and competing with key pluripotency factors. Taken together, these findings point out that c-Myc may significantly affect the genome-wide TF-DNA binding landscape, chromatin structure, and enhancer-promoter interactions.