PT  - JOURNAL ARTICLE
AU  - Scott Berry
AU  - Micha Müller
AU  - Lucas Pelkmans
TI  - Nuclear RNA concentration coordinates RNA production with cell size in human cells
AID  - 10.1101/2021.05.17.444432
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.17.444432
4099  - http://biorxiv.org/content/early/2021/05/17/2021.05.17.444432.short
4100  - http://biorxiv.org/content/early/2021/05/17/2021.05.17.444432.full
AB  - Unlike its DNA template, RNA abundance and synthesis rates increase with cell size, as part of a mechanism of cellular RNA concentration homeostasis. Here, we study this scaling phenomenon in human cells by combining genome-wide perturbations with quantitative single-cell measurements. Despite relative ease in perturbing RNA synthesis, we find that RNA concentrations remain highly constant. Systems-level analysis indicates that perturbations that would lead to increased nuclear mRNA abundance result in downregulation of mRNA synthesis. This is associated with reduced levels of several transcription-associated proteins and protein states that are normally coordinated with RNA production in single cells, including RNA polymerase II (Pol II) itself. Acute shut-down of nuclear RNA degradation, elevation of nuclear mRNA levels, and mathematical modelling indicate that mammalian cells achieve RNA concentration homeostasis by an mRNA-based negative feedback on transcriptional activity in the nucleus. Ultimately, this acts to robustly scale Pol II abundance with cell volume and coordinate mRNA synthesis and degradation.Competing Interest StatementLucas Pelkmans has filed a patent on the 4i technology, which is used in this manuscript (patent WO2019207004A1).