Some transcription factors can be both activators and repressors! Textbooks have been saying this for decades

This is another post about a bad press release based on a lack of knowledge of the history of the field.

Here's the press release from Washington State University as reported in SciTechDaily

Scientists Discover “Spatial Grammar” in DNA: Breakthrough Could Rewrite Genetics Textbooks

“Contrary to what you will find in textbooks, transcription factors that act as true activators or repressors are surprisingly rare,” said WSU assistant professor Sascha Duttke, who led much of the research at WSU’s School of Molecular Biosciences in the College of Veterinary Medicine.

Rather, the scientists found that most activators can also function as repressors.

“If you remove an activator, your hypothesis is you lose activation,” said Bayley McDonald, a WSU graduate student who was part of the research team. “But that was true in only 50% to 60% of the cases, so we knew something was off.”

Looking closer, researchers found the function of many transcription factors was highly position-dependent.

They discovered that the spacing between transcription factors and their position relative to where a gene’s transcription began determined the level of gene activity. For example, transcription factors might activate gene expression when positioned upstream or ahead of where a gene’s transcription begins but inhibit its activity when located downstream, or after a gene’s transcription start site.

... By integrating this newly discovered ‘spatial grammar,’ Christopher Benner, associate professor at UC San Diego, anticipates scientists can gain a deeper understanding of how mutations or genetic variations can affect gene expression and contribute to disease.

”The potential applications are vast,” Benner said. “At the very least, it will change the way scientists study gene expression.”

The story is based on a paper published in Nature.

Duttke, S.H., Guzman, C., Chang, M., Delos Santos, N.P., McDonald, B.R., Xie, J., Carlin, A.F., Heinz, S. and Benner, C. (2024) Position-dependent function of human sequence-specific transcription factors. Nature:1-8. [doi: 10.1038/s41586-024-07662-z]

Patterns of transcriptional activity are encoded in our genome through regulatory elements such as promoters or enhancers that, paradoxically, contain similar assortments of sequence-specific transcription factor (TF) binding sites1,2,3. Knowledge of how these sequence motifs encode multiple, often overlapping, gene expression programs is central to understanding gene regulation and how mutations in non-coding DNA manifest in disease4,5. Here, by studying gene regulation from the perspective of individual transcription start sites (TSSs), using natural genetic variation, perturbation of endogenous TF protein levels and massively parallel analysis of natural and synthetic regulatory elements, we show that the effect of TF binding on transcription initiation is position dependent. Analysing TF-binding-site occurrences relative to the TSS, we identified several motifs with highly preferential positioning. We show that these patterns are a combination of a TF’s distinct functional profiles—many TFs, including canonical activators such as NRF1, NFY and Sp1, activate or repress transcription initiation depending on their precise position relative to the TSS. As such, TFs and their spacing collectively guide the site and frequency of transcription initiation. More broadly, these findings reveal how similar assortments of TF binding sites can generate distinct gene regulatory outcomes depending on their spatial configuration and how DNA sequence polymorphisms may contribute to transcription variation and disease and underscore a critical role for TSS data in decoding the regulatory information of our genome.

The main finding is that a given transcription factor can act as either an activator or a repressor depending on where it binds in the promoter region. The lead author (Sascha Duttke) seems to think that this is a new finding that will require the re-writing of the textbooks. Christopher Benner (University of California, San Diego) thinks that their results "will change the way scientists study gene expression."

Really? I've been teaching that to undergraduates since the 1980s. Here's what I wrote in my 1994 textbook.

We have seen that CRP-cAMP can be both an activator and a repressor depending on which gene is being controlled. It functions as an activator when its binding site is just upstream of the promoter, but it functions as a repressor when the binding site overlaps the promoter and CRP-cAMP competes with RNA polymerase in binding DNA. There are many similar examples of regulatory proteins that can be both repressors and activators: one well-studied protein is AraC, which regulates genes involved in the utilization of arabinose. The regulation of arabinose operons is complex; by binding to different sites on DNA, AraC functions as either a repressor (in the absence of arabinose) or an activator (when arabinose is available).

Finally, MerR is a similar example of a regulatory protein that is both a repressor and an activator. The protein is required for the regulation of the mer operon, whose genes encode proteins that chelate mercury ions. MerR represses transcription of the mer operon by binding near the promoter. In the presence of mercury, a MerR-Hg²⁺ complex froms, and this complex acts directly as an activator at the same promoter.

My textbook doesn't have to be re-written although, in fairness, the information that I just quoted from the 1994 edition was left out of the more recent editions of the short version. Also, I couldn't find any recent textbooks that discuss this concept.

Here's the problem. We appear to have an entire generation of scientists who were never taught the basics of transcription regulation that were discovered in the 1960s and 1970s by scientists working with phage and bacteria. The classic example is the genetic switch in bacteriophage λ where one of the main regulatory proteins, λ repressor, acts both as a repressor of cro and as an activator of its own gene cI. There was a time when every student was taught the basics of transcription reglation in λ. Those stories seem to have been forgotten as most scientists concentrated on teaching eukaryotic biochemistry in the 1980s. This is why the researchers at Washington State University and the University of California, San Diego think they've discovered something new that will cause the textooks to be re-written.

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