{"about":{"site":"https://codewithpapers.app","non_affiliation":"Code with Papers and Syntology are not affiliated with, endorsed by, or sponsored by Papers with Code, Meta, or the pwc-archive mirror.","licence":"CC BY-SA 4.0","licence_url":"https://creativecommons.org/licenses/by-sa/4.0/legalcode","attribution":"https://codewithpapers.app/attribution","modified":"archive material modified by Syntology; see the attribution page"},"url":"/paper/ctrl-dna-controllable-cell-type-specific","title":"Ctrl-DNA: Controllable Cell-Type-Specific Regulatory DNA Design via Constrained RL","arxiv_id":"2505.20578","date":"2025-05-26","proceeding":null,"authors":["Xingyu Chen","Shihao Ma","Runsheng Lin","Jiecong Lin","Bo wang"],"abstract":"Designing regulatory DNA sequences that achieve precise cell-type-specific gene expression is crucial for advancements in synthetic biology, gene therapy and precision medicine. Although transformer-based language models (LMs) can effectively capture patterns in regulatory DNA, their generative approaches often struggle to produce novel sequences with reliable cell-specific activity. Here, we introduce Ctrl-DNA, a novel constrained reinforcement learning (RL) framework tailored for designing regulatory DNA sequences with controllable cell-type specificity. By formulating regulatory sequence design as a biologically informed constrained optimization problem, we apply RL to autoregressive genomic LMs, enabling the models to iteratively refine sequences that maximize regulatory activity in targeted cell types while constraining off-target effects. Our evaluation on human promoters and enhancers demonstrates that Ctrl-DNA consistently outperforms existing generative and RL-based approaches, generating high-fitness regulatory sequences and achieving state-of-the-art cell-type specificity. Moreover, Ctrl-DNA-generated sequences capture key cell-type-specific transcription factor binding sites (TFBS), short DNA motifs recognized by regulatory proteins that control gene expression, demonstrating the biological plausibility of the generated sequences.","url_abs":"https://arxiv.org/abs/2505.20578v1","url_pdf":"https://arxiv.org/pdf/2505.20578v1.pdf","source":{"archive":"pwc-archive (Hugging Face), CC BY-SA 4.0","snapshot":"2025-07-28","licence_url":"https://creativecommons.org/licenses/by-sa/4.0/legalcode","row_kind":"abstracts"},"code_links":[{"paper_slug":"ctrl-dna-controllable-cell-type-specific","repo_url":"https://github.com/bowang-lab/ctrl-dna","is_official":1,"mentioned_in_paper":1,"mentioned_in_github":1,"framework":"pytorch","reach":null}],"tasks":[{"task_slug":"reinforcement-learning-1","task_name":"Reinforcement Learning (RL)"},{"task_slug":"specificity","task_name":"Specificity"}],"methods":[],"datasets_introduced":[],"methods_introduced":[],"results":[],"syntology":{"atlas_url":null,"mcp":null,"developers":"https://syntology.ai/developers"},"arxiv_metadata":null,"syntology_extracted_results":null}