Evolution and Core Processes in Gene Regulation – some “terminal” thoughts (guest post from David Arnosti)

Guest appearance by David Arnosti here; I’m Ian’s colleague at Michigan State University and co-organizer for the ASBMB Special Symposium.

Our symposium last week brought together some folks who don’t regularly appear at the same conferences, including the structural biologists and biochemists who’ve devoted a good part of the last 30 years to unraveling the mechanisms of the central dogma – gene transcription, RNA metabolism, and protein translation. The trend has been to identify the central machinery, publish high-impact papers in single-word-title journals, and then years later discover that things don’t necessarily work the same in all contexts, organisms, developmental settings. Not surprising in eukaryotic transcription, for instance, where the “basal machinery” comprises ~200 proteins. Zach Burton, conference participant, refers to this complexity as a “molecular horror”, but from an evolutionary perspective, it is also an opportunity.

With respect to tracking the changes inherent in functioning of regulatory circuitry, we have more complete understanding of how bacterial systems work. Nice presentations by Saeed Tavazoie and Eduardo Groisman highlighted how easily such systems can transition between regulatory states, with just a few genetic changes in regulatory factors. Robert Landick and Seth Darst, in studies of E. coli RNA polymerase, pointed out that this bacterium actually features a novel outgrowth, an insertion of 188 amino acids that connects directly to the conserved trigger loop in the catalytic site. Nobody knows what it is doing there, but it is lineage specific, and mutations accumulate in this part of the protein when cells are grown under nutrient limitation, suggesting a short-circuit way to globally fiddle with gene expression.

Eukaryotic systems likewise have novel structures to their core machinery; Lawrence Myers described the gene amplification of Mediator subunits in Candida albicans that are linked to pathogenicity, while Jean-Marc Egly pointed out the pervasive effects of mutations in human Mediator and transcription factor TFIIH. With eukaryotes, the importance of variability in core machinery for generating important changes on the population or species level is obscure. Studies such as those presented by Ian Dworkin (host of this blog) and Aviv Regev showed how we are able to identify numerous loci involved in genetic background effects relating to development and immune function – but the overall importance of pervasive impacts generated by changes in an RNA polymerase subunit, for instance, vs. subtle changes in an enhancer is not clear. One mystery I dropped on the conferees was the special features of the RNA Pol II CTD found in Drosophila, but not other eukaryotes – a reflection of their unique developmental gene expression, discussed by Melissa Harrison and Julia Zeitlinger?

Aside from being mistaken once for Bill Gates by a visitor from Shanghai while walking around the University of Chicago, I was able to maintain my identity as a gene regulation specialist who takes to heart Theodosius Dobzhansky’s mantra that “Nothing in Biology Makes Sense Except in the Light of Evolution”. We will see how the combination of biochemical detail and evolutionary perspective can propel us into a future where gene regulation, in all its rich variation, makes sense. Many thanks to Joan Geiling and Barbara Gordon from the ASBMB for making this an outstanding conference!