Nucleosome-mediated cooperativity between transcription factors

TL;DR

This paper reveals that nucleosome competition can mediate cooperative binding of transcription factors, providing a flexible and modular mechanism that parallels hemoglobin's allosteric regulation, with broad implications for gene regulation and evolution.

Contribution

It introduces a nucleosome-mediated cooperativity model for TFs, paralleling the MWC model of hemoglobin, expanding understanding of gene regulation mechanisms.

Findings

Nucleosome competition enables TF cooperativity without direct interactions.

The mechanism aligns with the MWC model of hemoglobin.

Supports flexible, modular cis-regulatory regions in genomes.

Abstract

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.