Leonid Mirny: "How do proteins find and bind their sites on DNA?"

How do proteins find and bind their sites on DNA?

Coordinated regulation of gene expression relies on transcription factors (TFs) binding specific DNA sites.  Our large-scale information-theoretic analysis of more than 950 TF binding motifs demonstrates that prokaryotes and eukaryotes use strikingly different strategies to target TFs to specific genome locations. While bacterial TFs can recognize a specific DNA site in the genomic background, eukaryotic TFs exhibit widespread, nonfunctional binding and require clustering of sites to achieve specificity. We find support for this mechanism in a range of experimental studies and in our evolutionary analysis of DNA-binding domains.   Our systematic characterization of binding motifs provides new insights into the interpretation of functional genomic measurements.

In another study we examine interactions of transcription factors with nucleosomes. While nucleosomes limit the access of transcription factros to DNA, we show that they can also mediate cooperative binding by non-interacting factors.  We find that the mechanism of nucleosome-mediated cooperativity is identical to cooperativity in another multimolecular system – hemoglobin. This surprising analogy provides deep insights, with parallels between heterotropic regulation of hemoglobin (e.g. Bohr effect) and roles of nucleosome-positioning sequences and chromatin modifications in gene expression. Nucleosome-mediated cooperativity is consistent with several experimental studies, and provides a rationale for a broad range of genomic and evolutionary observations.

http://arxiv.org/abs/0901.2905
http://arxiv.org/abs/0812.3910