Intra-Complex Differential Transcription Strategies for Scaffold versus Effector Proteins

Scaffold-organized multi-protein complexes are major drivers of cellular regulatory pathways, but how the expression of their constituent genes is coordinated to support efficient assembly and cell-to-cell homeostasis remains poorly understood. Using snapTotal-seq data, this study addresses this issue at the transcription level through comparative analyses of stochastic transcription bursting – a major driver of expression level and primary source of its intrinsic cell-to-cell noise. We compared scaffold proteins and their effector partners in major regulatory multi-protein complexes: TNRC6A/B/C (in the miRISC complex) and CNOT1/2 (in the CCR4-NOT complex) in mRNA regulation; and AXIN1, APC, KSR2, AKAPs, DLG1, PATJ, HOMER1/2, and SQSTM1 in signal transduction. Our analyses reveal a shared strategy: compared to genes for active effector partner proteins and the general transcriptome, genes for structural scaffold proteins consistently utilize more frequent and smaller-sized bursting to achieve the fine tuning of a homeostatic expression level. This finding establishes a fundamental link between a protein’s physical role within a regulatory complex and the transcriptional bursting kinetics of its gene.