🧬 We have many foundation models or language models for DNAs, but can we control them? We introduce Ctrl-DNA: Controllable Cell-Type-Specific Regulatory DNA Design via Constrained RL — a reinforcement learning framework for controllable cis-regulatory sequence generation. Paper: Code: 🔬What’s the challenge? Designing regulatory DNA that is both highly... expressive in target cell types and inactive in others is essential for synthetic biology, gene therapy, and precision medicine. Yet, controlling these trade-offs is challenging due to sparse, sequence-level rewards and biological constraints. 🔥Why Ctrl-DNA? Ctrl-DNA fine-tunes pre-trained DNA language models using a value model free, Lagrangian-guided RL framework, enabling flexible and customizable constraint optimization. Users can define application-specific thresholds across cell types, balancing expression strength with specificity. ✅ Maximize target-cell expression ✅ Constrain off-target activity under user-defined thresholds ✅ Preserve cell-type-specific TF motif structure Benchmarked on human enhancer and promoter datasets, Ctrl-DNA consistently outperforms prior methods, achieving stronger specificity, higher fitness, and more biologically grounded sequence generation — all with direct control over regulatory trade-offs. Shoutout to the PhD students Xingyu Chen (Xingyu Chen ) and Rex Ma (Rex Ma) for their amazing work leading this project!show more

Bo Wang

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