Transcription factor clusters as information transfer agents

Precise regulation of gene expression requires accurate interpretation of nuclear transcription factor (TF) concentrations at DNA binding sites. While TF molecule clusters have been found to be associated with gene loci, the extent to which these clusters convey the nuclear concentration information to the gene locus and their functional implications remain unclear. In this work, we present evidence that the nuclear concentration gradient of Bicoid, a central transcription factor driving the anterior-posterior patterning genes during early fly development, is accurately reflected by the sub-nuclear clusters. This sub-nuclear clustering phenomenon yields a two-fold concentration amplification, significantly enhancing the accuracy of TF readout, and thereby facilitating precise nuclear positioning within the fly embryo. Furthermore, the characteristics of these clusters were found to be distinct from liquid-liquid phase separation. Notably, their physical sizes remain consistent throughout the embryo, while their concentrations change along the embryo's axis. We propose that TF clustering reduces the time required for the accurate interpretation of concentration. Thus TF clustering emerges as a mechanism enabling the rapid and precise assessment of cellular protein concentrations by gene enhancers. This mechanism offers an essential means for the transfer of positional information, which is fundamental to various biological processes.