‘Spooky’ Transcriptional Regulation?
Quantum Assumptions be Damned…
A perplexing ‘action at a distance’ has been observed in processes regulating gene transcription. Despite experimental observation, such action at a distance has hitherto evaded understanding. Pursuantly, in an attempt to place these observations within the realm of human comprehension, William Bialek and his biophysicist colleagues have offered up a theoretical treatise: Action at a distance in transcriptional regulation. Such a title teases assuming readers (e.g. myself) into anticipating that this ‘action at a distance’ is of the ‘spooky’ sort (i.e. ‘spooky’ as in the way Einstein described quantum entanglement), thus evoking expectations that quantum entanglement may play a role in regulating the readout of our genetic script.
Their article, however, serves as a vivid reminder that we should sometimes temper our mental autocomplete, and treat the term ‘action at a distance’ with the diligence it deserves. Quantum entanglement is but one example of action at a distance. There are others, and Bialek et al. point us towards the thermodynamically-driven kind.
Authors William Bialek, Thomas Gregor, and Gašper Tkačik conceive a theoretical description as to how protein droplets afford precise transcriptional control via leveraging action at a distance. In particular, they offer a model detailing how, by condensing around looped regions of DNA, protein-rich droplets can become energetically distinguishable from the solution that surrounds them (e.g consider oil droplets in water). Thus, by condensing out of the surrounding nucleoplasm, protein droplets descend down a thermodynamic trajectory, and enter a critically-banked regime¹ where action at a distance becomes permissible.
[1] For the sake of the discussion at hand, a critical regime can be taken as a place where a host of intriguing ‘critical phenomena’ (e.g. action at a distance) can occur.
Chemical Computers and Transcriptional Nodes
During development, exceedingly complex creatures (e.g. us humans) are pieced together cell-by-cell, protein-by-protein. The degree of exactitude needed to assemble all but the simplest organisms demands that gene transcription, the process via which DNA is copied into RNA, be regulated with astonishing precision. To this end, Nature has, as she so often does, arrived upon an intricate solution: Partition the nucleus into ‘transcriptional units’, and afford each unit to ability to regulate the transcription of specific genes. These units are, of course, the aforementioned protein droplets.
Our cells’ nuclei are packed with discrete, protein-dense droplets that serve as transcriptional units. Such a strategy accords with the notion that eukaryotic cells are innate chemical computers that evolution has iteratively optimized. Along these lines, by viewing protein droplets as transcriptional units, each droplet can be described as a computational node capable of integrating environmental cues and determining how many RNA copies to run off. Environment provides the input; quantity of RNA transcribed is the output.
Such is a blackbox description of transcriptional regulation. Bialek and colleagues, however, are primarily interested in prying open the blackbox and revealing the underlying biophysical principles.
A Droplet-based Transcriptional Dance
Shown below is a hypothetical protein drop as illustrated by Bialek et al. (Figure has been taken directly from Bialek et al.)
The droplets under consideration are protein-rich nodules containing the chemical constituents needed to control and enact gene transcription. Signaling molecules interact with and bind to certain genetic regions; they ‘dance’ with DNA! These signaling molecules, often referred to as transcription factors, are capable of binding with certain regulatory sites of DNA, known as enhancer sites. The binding of transcription factors to enhancer sites dynamically alters how things within the protein droplet are ‘wiggling’ about, and can increase the likelihood that a particular gene will be transcribed.
Transcription is initiated when a gene’s transcription gating region, or promoter site, encourages the binding of a protein called RNA polymerase, which walks along DNA and chains together the transcribed RNA sequence. Interestingly, however, interactions between transcription factors and enhancers can initiate transcription even when they occur away from the promoter site. In this regard, the ‘dances’ between enhancers and transcription factors cooperatively influence activity at the promoter, and do so in a droplet-wide manner. The enhancers and transcription factors thus form a contingent of promiscuously dancing ‘couples’. The promoter site can therefore be cast into the role of an all-seeing eye, which oversees the Transcriptional Dance, and modulates transcriptional output accordingly.
Modeling the Transcriptional Dance
This so-called Transcriptional Dance is what Bialek and colleagues are focused upon: Their work seeks to theoretically describe, as generally as possible, the rules governing it.
Every dance has rules, or idioms, by which it must abide (else we wouldn’t be able to differentiate a Samba from a Tango). The Transcriptional Dance is no different. Unto this notion, Bialek and co. theorize a model according to the following rules: a) the model must afford action at a distance; and, b) the model must adequately account for the salient features of transcriptional regulation.
Regarding the salient features underlying transcriptional regulation, Bialek et al. identify a singular characteristic: fine-tuned regulation in response to changes in transcription factor concentration. It has been observed that minuscule changes in the concentration of transcription factor can greatly influence transcriptional activity. As such, the protein droplets modeled by Bialek et al. are ‘on-edge’!
Critically-banked Regimes and Action at a Distance
To describe thermodynamic systems that are ‘on-edge’, scientists use a particular word: critical. Consequently, Bialek et al. equip their droplet model with a requirement of criticality. Hence why I chose the term ‘critically banked’ above. In addition to playing host to bizarre critical phenomena, critical regimes are poised upon a steep ridges.
Situated as such, small environmental perturbations can induce large sways in transcriptional output. Our Transcriptional Dance thus takes place on the precipice of criticality, where the mechanism of integration is ‘action at a distance’. Spatially localized interactions between transcription factors and enhancers are integrated, or ‘sensed’, droplet wide. Criticality thus lays the biophysical bedrock upon which transcriptional regulation can cooperatively (and precisely) proceed via action at a distance!
The Bigger (and Spookier?) Picture
Putting the work of Bialek et al. in broader context, a recent bolus of effort suggests that criticality may underlie many of life’s finely-tuned processes. Criticality has been postulated to be present across a range of biologically relevant scales: from the nanometer-sized protein droplets discussed here, to the long-range interactions between proteins embedded in lipid membranes, to neuronal function, all the way up to entire brains (i.e. the Critical Brain Hypothesis). Criticality is weird, and life is even weirder.
Moreover, emerging (and still-speculative) hypotheses have recently suggested that quantum criticality may underlie the very origins of protein-based life. Perhaps things are, after all, ‘spookier’ than they appear…
Check out the original work on arXiv: https://arxiv.org/abs/1912.08579
