RNA polymerase II dynamics and mRNA stability feedback scale mRNA amounts with cell size

• Published in: Cell 2023-11, Vol.186 (24), p.5254-5268.e26
• Main Authors: Swaffer, Matthew P., Marinov, Georgi K., Zheng, Huan, Fuentes Valenzuela, Lucas, Tsui, Crystal Yee, Jones, Andrew W., Greenwood, Jessica, Kundaje, Anshul, Greenleaf, William J., Reyes-Lamothe, Rodrigo, Skotheim, Jan M.
• Format: Article
• Language: English
• Subjects: cell biology; Cell Size; Feedback; RNA; RNA biology; RNA polymerase II; RNA Polymerase II - metabolism; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - metabolism; size scaling; systems biology; transcription; Transcription, Genetic
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2023.10.012

A fundamental feature of cellular growth is that total protein and RNA amounts increase with cell size to keep concentrations approximately constant. A key component of this is that global transcription rates increase in larger cells. Here, we identify RNA polymerase II (RNAPII) as the limiting factor scaling mRNA transcription with cell size in budding yeast, as transcription is highly sensitive to the dosage of RNAPII but not to other components of the transcriptional machinery. Our experiments support a dynamic equilibrium model where global RNAPII transcription at a given size is set by the mass action recruitment kinetics of unengaged nucleoplasmic RNAPII to the genome. However, this only drives a sub-linear increase in transcription with size, which is then partially compensated for by a decrease in mRNA decay rates as cells enlarge. Thus, limiting RNAPII and feedback on mRNA stability work in concert to scale mRNA amounts with cell size. [Display omitted] •Total mRNA must increase as a cell grows to ensure concentration homeostasis•RNAPII is the major dosage-limiting component of the transcriptional machinery in yeast•The size-dependent increase in RNAPII-DNA binding follows dynamic equilibrium kinetics•mRNA turnover decreases in larger cells to support mRNA concentration homeostasis mRNA transcription in budding yeast increases with cell size due to the equilibrium kinetics of dosage-limiting RNA polymerase II and the genome. This is then supported by a global increase in mRNA stability in larger cells to better scale mRNA amounts with cell size.