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PromAssist, synthetic biologists assistant




In previous posts, I briefly introduced the world of synthetic biology and designing of genetic circuits. The goal of competition such as iGEM is to encourage people designing creative solutions to real-world problems using synthetic biology with the hope of moving the field out of academia into industry, much like electronics. And much like electronics, iGEM is trying to develop a library of biological parts, analogous to electronic parts such as capacitors and resistors to build any circuit. If you have ever dabbled in electronics, you'd notice that not parts are created equally; Some capacitors have higher efficiencies than others which might suit a certain application more. In this post, I want to explore one of the most important "biological parts" in my opinion: 

 What are promoters

Promoters are regions of DNA usually found upstream of a gene that act as a switch to express whatever gene is downstream of it. Since translating DNA to mRNA requires the help of RNA polymerase, promoters job is to "attract" floating RNA polymerase and get it attached to so it can translate its downstream gene or genes (figure 1).

Figure 1: Simple sketch explaining promoters


 The simplest form of promoters are called constitutive promoters, or more directly unregulated promoters. Those promoter attract floating σ70 RNA polymerase (sometimes called housekeeping RNAP), they are unregulated as they are usually crucial to the survival of the cell. Things get way more complicated when these promoters are inducible, meaning they can be regulated by other proteins or molecules. A classic textbook example is the lactose operon (commonly known as lac operon) in E coli used to metabolise lactose in the absence of glucose. Since it is energetically expensive to produce lactase when glucose is abundant, the lac operon, which is a group of genes controlled by a single promoter, is mostly repressed. The way it works is roughly like this:
 
Figure 2: Lac operon dynamics. Source: Microbenotes


  1. Lac respressor, which is a DNA-binding protein is always expressed – downstream of a constitutive promoters (figure 2a).
  2. The Lac repressor binds to the Lac operon promoter, blocking RNA polymerase from attaching (figure 2a). 
  3. If lactose molecules are present, it binds to the Lac repressor and unblocks it from the promoter region (figure 2b).
  4. RNA polymerase can do its job of translating the operon genes into mRNA (figure 2b). 

 This is a beautifully evolved system that acts as an if statement in modern engineering talk. In fact, the lac operon was the first discovery of gene regulatory networks and it awarded its discoverers a Nobel prize in Physiology in 1965. 

Why promoters are important and how can PromAssist can help

Because the lac operon is quite well understood, synthetic biologist have been using the lac operon system to express their gene of choice in E. coli, usually replacing lactose with IPTG as it has a similar structure to lactose and can be used to inactivate the lac repressor. While it works on a simple on/off genetic circuits, it can be daunting if you want to create more complex circuits with multiple triggers and you desire high specificity in gene expression. Synthetic promoter, designed specifically for certain repressors, which can also be synthetic (as in not found in nature) can unlock endless possibilities for creating highly crafted and tuned circuits. Just like how AlphaFold can assist scientist in visualising the 3D shape of proteins, hence the binding affinity in proteins like lac repressors, PromAssist, can be a useful tool for scientists experimenting with different synthetic promoter to assist the strength of transcription factor binding and gene expression strength in general.  

PromAssist is based on DNABERT, which is a BERT-based machine learning model pre-trained on massive amount of DNA sequences, I have fined-tuned the model on data gathered from this paper, the goal is for scientists to input a certain DNA sequence for the promoter in mind and it should output the relative strength of its gene expression. The hope is that this tool can help biologist find a suitable synthetic promoter much quicker with the aid of PromAssist. The model will be updated as new fine-tuning strategies are used.

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