Effective in vivo diffusion constant of DNA-binding transcription factors

Determine the effective three-dimensional diffusion constant of DNA-binding transcription factors during in vivo target-site search within the nucleus, explicitly accounting for interactions with the nuclear milieu such as macromolecular crowding and transient non-specific DNA binding, so that facilitated diffusion models can be quantitatively parameterized with experimentally validated values of D_TF^{eff}.

Background

The paper analyzes transcription factor target search using a facilitated diffusion model that combines one-dimensional sliding along DNA with three-dimensional excursions in the nucleoplasm. In this framework, the overall search time depends critically on the effective three-dimensional diffusion constant, D_TF^{eff}, which encapsulates the impacts of crowding, transient non-specific DNA interactions, and other nuclear environmental factors.

While the authors provide illustrative calculations using a plausible range for D_TF^{eff} based on available measurements, they explicitly note that determining this parameter remains unresolved. Accurately measuring D_TF^{eff} is essential for testing and refining quantitative predictions of facilitated diffusion and for comparing model outcomes against in vivo dynamics across organisms and cell types.