Gene copy number and negative feedback differentially regulate transcriptional variability of segmentation clock genes

Timely progression of a genetic program is critical for embryonic development. However, gene expression involves inevitable fluctuations in biochemical reactions leading to substantial cell-to-cell variability (gene expression noise). One of the important questions in developmental biology is how pattern formation is reproducibly executed despite these unavoidable fluctuations in gene expression. Here, we studied the transcriptional variability of two paired zebrafish segmentation clock genes (her1 and her7) in multiple genetic backgrounds. Segmentation clock genes establish an oscillating self-regulatory system, presenting a challenging yet beautiful system in studying control of transcription variability. In this study, we found that a negative feedback loop established by the Her1 and Her7 proteins minimizes uncorrelated variability whereas gene copy number affects variability of both RNAs in a similar manner (correlated variability). We anticipate that these findings will help analyze the precision of other natural clocks and inspire the ideas for engineering precise synthetic clocks in tissue engineering.