  Cooperative binding of transcription factors (TFs) to cis-regulatory regions
(CRRs) is essential for precision of gene expression in development and other
processes. The classical model of cooperativity requires direct interactions
between TFs, thus constraining the arrangement of TFs sites in a CRR. On the
contrary, genomic and functional studies demonstrate a great deal of
flexibility in such arrangements with variable distances, numbers of sites, and
identities of the involved TFs. Such flexibility is inconsistent with the
cooperativity by direct interactions between TFs. Here we demonstrate that
strong cooperativity among non-interacting TFs can be achieved by their
competition with nucleosomes. We find that the mechanism of nucleosome-mediated
cooperativity is mathematically identical to the Monod-Wyman-Changeux (MWC)
model of cooperativity in hemoglobin. This surprising parallel 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 regulation. Characterized mechanism is consistent with
numerous experimental results, allows substantial flexibility in and modularity
of CRRs, and provides a rationale for a broad range of genomic and evolutionary
observations. Striking parallels between cooperativity in hemoglobin and in
transcription regulation point at a new design principle that may be used in
range of biological systems.
