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🤔How do you design a promoter for stable titration of expression? 💡Try programmable promoter editing with DIAL! 📰Now published at @NatureBiotech 🧵 [1/n] 🔗 below
TL/DR: 1. DIAL, a synthetic promoter system, edits the promoter to generate a range of unimodal setpoints [2/n]
📏DIAL setpoints are unimodal, robust to varying levels of ZFa [3/n]
DIAL transmits transient inputs into heritable states [4/n]
This allowed us to identify a mild selection dosage-dependent selection effect from the fluorescent protein mGreenLantern. Note, fraction of cells at the low setpoint increases (selective expansion) compared to the high setpoint. [5/n]
🙌TET-DIAL system enables small-molecule activation of defined setpoints so you can titrate and generate pulses at different setpoint! [6/n]
🏵️DIAL controls expression in primary cells and iPSCs; regulates physiologically-relevant transgenes. [7/n]
📏DIAL setpoints map fine-scale changes in regulator expression to rates of cell-fate transition. This was the biggest update to the preprint! Could we get stable expression through a cell fate conversion? Such that we cut set cell on different trajectories and get different rates of conversion? Yes we could and yes we did! [8/n]
🧫 Why is this important? While (in theory) there are many dosage-dependent genes, tools to identify them and control them have been limiting. With DIAL, we can induce setpoints and ask how those setpoints change long-term outcomes like reprogramming. [9/n]
You can see the original tweetorial 🧵here with lots more details and still more in the final version [10/n] <a target="_blank" href="https://x.com/GallowayLabMIT/status/1820472906239054260" color="blue">x.com/GallowayLabMIT…</a>
Also, Anne Trafton from MIT News provided a nice write here! <a target="_blank" href="https://tinyurl.com/DIALMIT" color="blue">tinyurl.com/DIALMIT</a> [11/n]
📢Want to hear more? Check out the briefing! With some nice words from @MoKhalilLab who’s foundational work with synthetic promoters inspired us [12/n] <a target="_blank" href="https://tinyurl.com/DIALBrief" color="blue">tinyurl.com/DIALBrief</a>
🙏Thanks to the team at NBT @NatureBiotech especially Barbara Cheifet, our editor, who helped us develop this story and get good, constructive feedback which helped improve the story and the tools! [13/n] <a target="_blank" href="https://x.com/NatureBiotech/status/1977813798460477713" color="blue">x.com/NatureBiotech/…</a>
💵Thanks also to our funders NIH, NSF, AFOSR, ICB (Army). We truly could not have done it without their support and we are very grateful especially in these challenging times! [14/n]
🥳Congrats to @science_sneha who lead this project and coordinated the team – Yunbeen, Mary, Brittany, Adam, Emma, Kasey, and Deon—who helped us cross the finish line! Excelsior! [15/n]
