Immune complexity: gene expression like dimmer switch (Introduction)

by David Turell , Thursday, April 15, 2021, 21:32 (1106 days ago) @ David Turell

A carefully designed system to modify but not suppress gene activity expression:

https://science.sciencemag.org/content/372/6539/292?utm_campaign=toc_sci-mag_2021-04-15...

"A transcriptional control mechanism in yeast that allows cells to respond to changes in nutrient concentrations works very much like a household light-dimmer switch. That is, the system separately controls whether gene expression is “on” or “off” and the extent of gene expression. The galactose-responsive pathway is activated when yeast need to switch from metabolizing glucose to metabolizing galactose. Ricci-Tam et al. found that, rather than using two separate elements for the switch and dimmer controls, yeast use a single transcription factor, Gal4p, separately regulating its abundance (through transcriptional regulation) and its catalytic activity (through interaction with a protein-binding partner). Such regulation may be common and can allow responses to the environment on physiological and evolutionary time scales.

"Abstract
Gene-regulatory networks achieve complex mappings of inputs to outputs through mechanisms that are poorly understood. We found that in the galactose-responsive pathway in Saccharomyces cerevisiae, the decision to activate the transcription of genes encoding pathway components is controlled independently from the expression level, resulting in behavior resembling that of a mechanical dimmer switch. This was not a direct result of chromatin regulation or combinatorial control at galactose-responsive promoters; rather, this behavior was achieved by hierarchical regulation of the expression and activity of a single transcription factor. Hierarchical regulation is ubiquitous, and thus dimmer switch regulation is likely a key feature of many biological systems. Dimmer switch gene regulation may allow cells to fine-tune their responses to multi-input environments on both physiological and evolutionary time scales.

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"Our results support a “hierarchically decoupled regulation” model in which the abundance and activity of a single transcription factor, Gal4p, are regulated independently. In this model, transcriptional regulation of Gal4p abundance by the upstream transcription factor Mig1p mediates the response to glucose, whereas protein binding of Gal80p to Gal4p regulates Gal4p activity in response to the galactose:glucose ratio. Unlike our initial chromatin-decoupled regulation model, a single transcription factor, Gal4p, controlled both the switch and the rheostat at the final step of the pathway. In both models, decoupling was achieved by regulation working through two distinct mechanisms; this is reminiscent of other cases, such as the frequency versus amplitude modulation of the Msn2p-Msn4p stress responses in yeast. Our model is agnostic to mechanistic details of how Gal4p activates downstream GAL promoters and is thus compatible with recent observations that different Gal4p-binding sites have different functional roles.

"What physiological function could be served by decoupling the on-off switch of pathway activation from the expression level of the pathway? When faced with mixtures of sugars, yeast first use glucose, then less-preferred carbon sources, a phenomenon called diauxic growth. Yeast prepare by expressing GAL genes before glucose is depleted; the earlier a strain expresses GAL genes, the higher the fitness advantage it has once glucose is depleted. However, preparation comes at a fitness cost in the period before the glucose runs out. One possible function of the decoupled switch-and-rheostat design is to allow early activation of the pathway but with a reduced cost.

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"Decoupled control is a useful property because it allows response features to be independently controlled physiologically and evolutionarily. Decoupling has often been proposed to involve independent transcription factor–binding sites on promoters and to be aided by chromatin. We show here that the same result can be accomplished by hierarchical regulation of the abundance and activity of a transcription factor. Because regulation of this kind is common, it is likely that decoupling of responses is also achieved by this mechanism in other systems."

Comment: Another very carefully designed system which creates gene expression activity depending on different sugar concentrations. We can see how is is done step by step, but still have no way of understanding the underlying mechanisms of control. That is still a total black box