Impact of relative dose intensity of standard regimens on survival in elderly patients aged 80 years and older with diffuse large B cell lymphoma

Abstract Concentration of transcription factors (TFs) and their cell-to-cell protein variability are important functional determinants in development, yet how variability is controlled remains poorly understood. Using Fluorescence Correlation Spectroscopy (FCS), we characterized in live Drosophila imaginal discs the concentration and cell-to-cell variability of 14 endogenously tagged TFs. We found that the Hox TF Antennapedia (Antp) transitioned from a low concentration/high variability state early in development to a high concentration/low variability state later in development. Using FCS and temporally resolved genetic studies, we uncovered that Antp is necessary and sufficient to drive a developmental regulatory switch from auto-activation to auto-repression, thereby reducing variability. This switch is controlled by a progressive change in relative concentrations of preferentially activating and repressing Antp protein isoforms, which bind to chromatin with different affinities. We derived a simple mathematical model, confirming that the Antp auto-regulatory circuit would suffice to increase protein concentration while suppressing variability over time.