Feedback from nuclear RNA on transcription promotes robust RNA concentration homeostasis in human cells

Mechanisms of cellular mRNA transcript homeostasis

“…This approach labels all RNA synthesized during the pulse and thereby provides a measure of the bulk RNA production rate of the cell. Image-based approaches combining this with measurement of cell volume and cell-cycle stage in human cells revealed that overall RNA production rates increase almost proportionally with cell size, but also suggested differences between cell-cycle stages -S-phase and G2-phase cells showed increased RNA synthesis rates compared to G1-phase cells of the same volume [12]. This is reminiscent of earlier Box…”

“…In these cases, mRNA abundance changes are coordinated with changes in cell size [14][15][16], indicating that mRNA concentration is maintained despite changes in cell size. Moreover, a recent imagebased screen in human cells across hundreds of genetic perturbations also revealed that total cellular RNA and mRNA abundances typically remain stable even when cell size or bulk RNA production rates are dramatically altered [12,17]. mRNA abundance is therefore closely and robustly linked to cell size to maintain constant concentrations of mRNA transcripts (Figure 1B).…”

“…that the changes in cell size are within a twofold range of the wild-type value. Likewise, in mammals, pulse labeling in rat tissues [13] and human cell culture [12] showed that increased RNA content of larger cells was accompanied by a proportional increase in RNA production. Moreover, using an inhibitor of cyclin-dependent kinases to disrupt cell-cycle progression in human cells leads to larger cells [26] with proportionally increased RNA production rates [12].…”

“…RNA metabolism, cell size, and the cell cycle are closely linked, so interpretation of the outcome of perturbations must account for changes in cell size and cell-cycle distribution, and carefully distinguish concentration from abundance. [7], Arabidopsis thaliana [8], Caenorhabditis elegans [9], and human cells [9][10][11][12]. With a few notable exceptions (Box 1), these experiments have revealed that gene-specific transcript abundance is generally coordinated with cell sizeknown as size-scaling.…”

“…Metabolic pulse labeling has been applied at the single-cell level in human cells [9,12] and in Rana pipiens motoneurons [29]. This approach labels all RNA synthesized during the pulse and thereby provides a measure of the bulk RNA production rate of the cell.…”