Can the functions of upregulated genes, revealed by a transcriptomic study, be interpreted in a contradictory manner?

19 July 2024 3 8K Report

When culturing bacteria and comparing two conditions—one with a specific substrate and one without—transcriptomic studies can indicate which proteins play a role in the metabolic pathway of the available substrate. However, I am curious if the absence of a substrate could also lead to the upregulation of genes relevant to the metabolic pathway associated with the missing substrate.

For example, consider two conditions: Condition A lacks substrate A but has substrate B, leading to a shortage of substrate XY. As a result, a protein (let's call it protein C) is involved in overcoming this shortage or regenerating/producing substrate XY, and therefore is highly expressed, even though substrate A is absent, which is ultimately necessary to produce the limited substrate XY. Thus, the transcriptomic study would show an upregulation of the gene encoding protein C for the condition where substrate B is present. However, protein C plays a crucial role in the metabolic pathway of substrate A, not substrate B.

Is this a scenario that could possibly occur, or is it unlikely? I understand that in science, it's difficult to say "never." Please provide scientific arguments for why this might or might not be the case.

Qasim Ali

This scenario is plausible and can indeed occur in microbial metabolic regulation. Here’s a detailed explanation of why this might happen, supported by scientific arguments:

Regulatory Mechanisms in Microbial Metabolism

Microbial cells often display intricate regulatory mechanisms to adapt to changes in their environment, including the availability of substrates. These mechanisms include:

Catabolite Repression and Activation:Catabolite Repression: This is a regulatory mechanism where the presence of a preferred carbon source (like glucose) suppresses the expression of genes involved in the metabolism of other, less preferred carbon sources. Inducer Exclusion: In the absence of a preferred substrate, the expression of genes involved in the metabolism of alternative substrates can be upregulated to allow the cell to utilize the available substrates.

Global Regulatory Networks:Sigma Factors and Transcriptional Regulators: Bacteria have global regulatory systems involving sigma factors and transcriptional regulators that respond to environmental changes and coordinate the expression of multiple genes, including those involved in different metabolic pathways.

Potential Scenarios Leading to Gene Upregulation

Absence of Substrate Leading to Upregulation of Related Pathways:Adaptive Response: When a specific substrate (substrate A) is absent, the cell might upregulate pathways that are tangentially related to substrate A to adapt to the shortage. For instance, if substrate A is needed to produce substrate XY, the cell might upregulate pathways or genes (like the gene for protein C) involved in producing or recycling substrate XY from other available resources (like substrate B).

Cross-Pathway Regulation:Regulatory Crosstalk: Metabolic pathways are often interconnected. The lack of substrate A might lead to a regulatory response where pathways involving substrate B are upregulated to compensate for the metabolic imbalance. This can include the upregulation of genes that are part of substrate A's metabolic pathway but have roles in managing the scarcity of substrate XY.

Resource Allocation and Stress Response:Stress Response Mechanisms: The absence of a critical substrate can trigger a stress response, leading to the upregulation of genes involved in mitigating this stress. Protein C, in your example, might be part of a broader stress response system aimed at overcoming metabolic shortages, hence its increased expression.

Scientific Arguments Supporting This Scenario

Empirical Evidence:Transcriptomic Studies: Numerous transcriptomic studies have shown that the absence of a specific substrate can lead to the upregulation of genes not directly related to the immediate substrate but part of interconnected metabolic pathways. For example, E. coli shows complex regulatory responses to nutrient limitations involving multiple genes and pathways.

Metabolic Flexibility:Metabolic Network Models: Computational models of metabolic networks, such as flux balance analysis (FBA), often predict that cells rewire their metabolism in response to substrate availability. These models can show upregulation of alternative pathways to ensure survival and metabolic balance.

Evolutionary Adaptation:Adaptive Evolution: Microorganisms have evolved to efficiently adapt to fluctuating environmental conditions. The upregulation of seemingly unrelated genes can be part of an adaptive strategy to maximize the utilization of available resources and ensure cellular homeostasis.

Conclusion

The scenario you described, where the absence of a specific substrate leads to the upregulation of genes relevant to its metabolic pathway due to the presence of an alternative substrate, is scientifically plausible. This can be explained by the complex regulatory mechanisms, adaptive responses, and interconnected nature of metabolic pathways in microorganisms. Transcriptomic studies are invaluable in revealing these intricate regulatory networks and understanding the cellular responses to environmental changes.

Stefanie Becker

Thank you for your effort in answering my question. I was hoping someone would share a similar observation that I could reference in a scientific publication. Alternatively, if there is a review on the interpretation of transcriptomics data that you could recommend, that would be helpful. I had similar experiences when asking an AI, but they tend to agree with my ideas too closely, which is not what I am looking for.

Michael Kohlstedt

Dear Stefanie,

from my experience there are scenarios where cells express genes that allow for the degradation of potential substrates which might not be present in the medium as part of a general stress or starvation response. This is the case for example in Bacillus subtilis which expresses genes of the DegU regulon comprising the upregulation of degradative enzymes like (proteases, peptidases, levansucrase, etc.) upon carbon depletion or entry into the stationary phase.

https://subtiwiki.uni-goettingen.de/wiki//index.php?title=DegU_regulon

https://pubmed.ncbi.nlm.nih.gov/12471443/

Also catabolite control or repression can mediate such a response (e.g. via cAMP in E. coli oder CcpA in B. subtilis).

https://subtiwiki.uni-goettingen.de/v4/regulon?id=protein:E39AFEB7B7F28969A35C4B51CC6E7819F71C79D9

https://pubmed.ncbi.nlm.nih.gov/11251851/

Best

Michael

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