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  • Gene regulation gravitates toward either addition or multiplication when combining the effects of two signals.

Gene regulation gravitates toward either addition or multiplication when combining the effects of two signals.

eLife (2020-12-08)
Eric M Sanford, Benjamin L Emert, Allison Coté, Arjun Raj
ABSTRACT

Two different cell signals often affect transcription of the same gene. In such cases, it is natural to ask how the combined transcriptional response compares to the individual responses. The most commonly used mechanistic models predict additive or multiplicative combined responses, but a systematic genome-wide evaluation of these predictions is not available. Here, we analyzed the transcriptional response of human MCF-7 cells to retinoic acid and TGF-β, applied individually and in combination. The combined transcriptional responses of induced genes exhibited a range of behaviors, but clearly favored both additive and multiplicative outcomes. We performed paired chromatin accessibility measurements and found that increases in accessibility were largely additive. There was some association between super-additivity of accessibility and multiplicative or super-multiplicative combined transcriptional responses, while sub-additivity of accessibility associated with additive transcriptional responses. Our findings suggest that mechanistic models of combined transcriptional regulation must be able to reproduce a range of behaviors.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Transforming Growth Factor-β1 human, TGF-β1, recombinant, expressed in CHO cells, powder, suitable for cell culture
SAFC
Formaldehyde solution, contains 10-15% methanol as stabilizer, 37 wt. % in H2O
Sigma-Aldrich
Retinoic acid, ≥98% (HPLC), powder
Sigma-Aldrich
Anti-RARA antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody