Conventional gene expression regulation occurs via the activation or repression of gene promoters. We have discovered that constrained synthesis of messenger RNA molecules through limited nucleotide availability also affects expression. Multiple drugs, biological effectors, pollutants and disease states appear to affect nucleotide availability, adding a new dimension to pharmacological action, adverse effects, gene x environment interaction, and pathology. Deducing the precise mechanism(s) and consequences of this biochemical disturbance are my research group’s main goals. 

I recently published a paper that describes a novel mechanism of gene expression control that doesn't act through individual gene promoters but acts instead on the capacity of the cell to synthesise mRNAs from constituent nucleotides. You can imagine that, if a nucleotide is in short supply, then mRNA transcripts more enriched in that particular nucleotide will be harder to synthesise and therefore expressed at a lower level. So, this form of gene expression regulation acts by combining supply (of nucleotides) and demand (of each mRNA and its composition) to produce a global change in expression profile. Genes at the extremes of composition will be most affected by this mechanism and I observe that many of them fall into biological pathways and processes (immune, metabolic, reproductive etc.) that might need a ‘hardwired’ form of regulation like this – so clearly evolution has selected for strange compositions in certain genes.

However, I have observed that many common diseases, drugs, viral infections, the menstrual cycle, circadian rhythms, and environmental pollutants all seem to perturb global expression through this mechanism. This suggests that each of these phenomena alter available nucleotide levels in cells – perhaps by direct competition during synthesis (e.g., nucleotide analogues) or through inhibition of nucleotide biochemistry.

In terms of drugs and environmental pollutants, approximately 20% of them perturb global gene expression, and they can do this in one of two directions (think of a children’s see-saw). This is because they can increase or decrease nucleotide availability. Antibiotics are a good example of medications that can do this, and there are examples of these drugs that ‘push’ the global gene expression see-saw in either direction. For example, we have seen methicillin and tetracycline acting in different directions.

Multiple projects are needed to further our understanding of this phenomenon. Do some drugs confer risk of, or protect against, the diseases which feature global gene expression changes? How does this mechanism and the established mechanisms of epigenetic regulation of gene expression interact? What is/are the precise biochemical dysfunction(s) of nucleotide synthesis underlying the effect?

A mechanism of global gene expression regulation is disrupted by multiple disease states and drug treatments

Further information

Background in genetics, molecular biology, bioinformatics would be advantageous.