DNA-induces intra- and inter-molecular changes in dimerization of the human FOXP1

Transcription factors (TFs) are proteins that regulate gene expression by binding to specific DNA sequences and gating access to genes. This paradigm implies a one-directional gene regulation of DNA remodeling via TFs and their cofactors. Here, we present an example in which the DNA modulates the kinetics of dimerization of the forkhead (FKH) domain of the FoxP1 human TF, favoring its monomeric form over its domain-swapped dimer conformation. Hence, challenging the one-dimensional remodeling paradigm. To inquire about the structural dynamics of the FKH domain in its dimeric form and the presence of DNA, we use molecular dynamics simulations, single-molecule multiparameter fluorescence spectroscopy, and biochemical assays. We found that the monomeric form of the FoxP1 FKH domain primarily displays a disordered-like behavior, which is allosterically reverted by dimerization. Interestingly, DNA favors its interaction with the FKH in its monomeric form over its domain-swapped dimer at the cost of decreasing the FKH domain structural stability. Our findings imply that gene expression is tightly regulated by a negative feedback control over suppressor proteins such as FoxP1 by introducing a bidirectional control over gene expression. Moreover, it suggests that FoxP1 gene suppression action in its domain-swapped conformation, which brings together distant DNA segments and locks transcription access, requires the presence of other dimerization domains, cofactors, or the nuclear macromolecular composition to revert the negative feedback exerted by the DNA.