{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:49:58Z","timestamp":1791521398798,"version":"4.3.4"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":253,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Interpretability is not optional in biology: understanding gene regulation requires models whose learned structure can be directly interrogated, not merely accurate predictors whose internals resist mapping onto regulatory relationships. We ask whether an architecture mirroring the central dogma yields attention and gradient maps that recover known regulatory elements and networks in inspectable form.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Central Dogma Transformer II (CDT-II) mirrors the central dogma in its architecture\u2014DNA self-attention, RNA self-attention, and DNA-to-RNA cross-attention\u2014requiring only genomic embeddings and raw per-cell expression. On K562 CRISPR interference (CRISPRi) data with five genes held out entirely, CDT-II predicts perturbation effects (per-gene mean r\u2009=\u20090.84), recovers the GFI1B regulatory network (6.6-fold enrichment, P\u2009=\u20093.5\u00d710\u221217), and concentrates cross-attention on ENCODE regulatory elements including CTCF sites (mean 7.67\u00d7 across 28 target genes, P&amp;lt;.001). Gradient attribution predicts consequences of perturbing therapeutic targets (mean r\u2009=\u20090.82). For TFRC, target of the anti-TfR1 antibody PPMX-T003, it identifies erythrocyte-structure, iron-dependent DNA-synthesis and oxidative-stress genes, matching anemia and ferroptosis reported clinically and preclinically\u2014without clinical data as input. CDT-II acts as an AI microscope, surfacing clinically relevant regulatory structure from perturbation experiments alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>Source code is available at https:\/\/github.com\/nobusama\/CDT2. Pre-computed embeddings, training data, and model weights are available at https:\/\/huggingface.co\/datasets\/nobusama17\/CDT2-data<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioadv\/vbag268","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:48:47Z","timestamp":1789040927000},"source":"Crossref","is-referenced-by-count":0,"title":["Central Dogma Transformer II: an AI microscope for understanding cellular regulatory mechanisms"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6570-9450","authenticated-orcid":false,"given":"Nobuyuki","family":"Ota","sequence":"first","affiliation":[{"name":"Independent Researcher , Burlingame, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"2026100900062172500_vbag268-B1","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: single-cell regulatory network inference and clustering","volume":"14","author":"Aibar","year":"2017","journal-title":"Nat Methods"},{"key":"2026100900062172500_vbag268-B2","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat Genet"},{"key":"2026100900062172500_vbag268-B3","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1038\/s41588-021-00782-6","article-title":"Base-resolution models of transcription-factor binding reveal soft motif syntax","volume":"53","author":"Avsec","year":"2021","journal-title":"Nat Genet"},{"key":"2026100900062172500_vbag268-B4","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1038\/s41592-021-01252-x","article-title":"Effective gene expression prediction from sequence by integrating long-range interactions","volume":"18","author":"Avsec","year":"2021","journal-title":"Nat Methods"},{"key":"2026100900062172500_vbag268-B5","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1038\/s41586-025-10014-0","article-title":"Advancing regulatory variant effect prediction with AlphaGenome","volume":"649","author":"Avsec","year":"2026","journal-title":"Nature"},{"key":"2026100900062172500_vbag268-B6","doi-asserted-by":"publisher","first-page":"P10008","DOI":"10.1088\/1742-5468\/2008\/10\/P10008","article-title":"Fast unfolding of communities in large networks","volume":"2008","author":"Blondel","year":"2008","journal-title":"J Stat Mech"},{"key":"2026100900062172500_vbag268-B7","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/227561a0","article-title":"Central dogma of molecular biology","volume":"227","author":"Crick","year":"1970","journal-title":"Nature"},{"key":"2026100900062172500_vbag268-B8","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1038\/s41592-024-02201-0","article-title":"scGPT: toward building a foundation model for single-cell multi-omics using generative AI","volume":"21","author":"Cui","year":"2024","journal-title":"Nat Methods"},{"key":"2026100900062172500_vbag268-B9","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1016\/j.cell.2016.11.038","article-title":"Perturb-Seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens","volume":"167","author":"Dixit","year":"2016","journal-title":"Cell"},{"key":"2026100900062172500_vbag268-B10","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature11082","article-title":"Topological domains in mammalian genomes identified by analysis of chromatin interactions","volume":"485","author":"Dixon","year":"2012","journal-title":"Nature"},{"key":"2026100900062172500_vbag268-B11","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"ENCODE Project Consortium","year":"2012","journal-title":"Nature"},{"key":"2026100900062172500_vbag268-B12","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1038\/s41576-019-0122-6","article-title":"Deep learning: new computational modelling techniques for genomics","volume":"20","author":"Eraslan","year":"2019","journal-title":"Nat Rev Genet"},{"key":"2026100900062172500_vbag268-B13","doi-asserted-by":"publisher","first-page":"151564","DOI":"10.1016\/j.bbrc.2025.151564","article-title":"Anti-transferrin receptor antibody (JST-TFR09\/PPMX-T003) induces ferroptosis in adult T-cell leukemia\/lymphoma (ATLL) cells","volume":"756","author":"Fauzi","year":"2025","journal-title":"Biochem Biophys Res Commun"},{"key":"2026100900062172500_vbag268-B14","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1038\/s41588-019-0538-0","article-title":"Activity-by-contact model of enhancer\u2013promoter regulation from thousands of CRISPR perturbations","volume":"51","author":"Fulco","year":"2019","journal-title":"Nat Genet"},{"key":"2026100900062172500_vbag268-B15","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.cell.2018.11.029","article-title":"A genome-wide framework for mapping gene regulation via cellular genetic screens","volume":"176","author":"Gasperini","year":"2019","journal-title":"Cell"},{"key":"2026100900062172500_vbag268-B16","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.cell.2013.06.044","article-title":"CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes","volume":"154","author":"Gilbert","year":"2013","journal-title":"Cell"},{"key":"2026100900062172500_vbag268-B17","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.18653\/v1\/N19-1357","author":"Jain","year":"2019"},{"key":"2026100900062172500_vbag268-B18","doi-asserted-by":"publisher","first-page":"D498","DOI":"10.1093\/nar\/gkz1031","article-title":"The reactome pathway knowledgebase","volume":"48","author":"Jassal","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2026100900062172500_vbag268-B19","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"2026100900062172500_vbag268-B20","doi-asserted-by":"publisher","first-page":"e91","DOI":"10.1093\/nar\/gkae783","article-title":"DNA breathing integration with deep learning foundational model advances genome-wide binding prediction of human transcription factors","volume":"52","author":"Kabir","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"2026100900062172500_vbag268-B21","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1038\/s41586-022-05688-9","article-title":"Dissecting cell identity via network inference and in silico gene perturbation","volume":"614","author":"Kamimoto","year":"2023","journal-title":"Nature"},{"key":"2026100900062172500_vbag268-B22","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"2026100900062172500_vbag268-B23","doi-asserted-by":"publisher","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: a comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2026100900062172500_vbag268-B24","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/s41588-024-02053-6","article-title":"Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation","volume":"57","author":"Linder","year":"2025","journal-title":"Nat Genet"},{"key":"2026100900062172500_vbag268-B25","author":"Loshchilov","year":"2019"},{"key":"2026100900062172500_vbag268-B26","doi-asserted-by":"publisher","first-page":"e11517","DOI":"10.15252\/msb.202211517","article-title":"Predicting cellular responses to complex perturbations in high-throughput screens","volume":"19","author":"Lotfollahi","year":"2023","journal-title":"Mol Syst Biol"},{"key":"2026100900062172500_vbag268-B27","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1109\/BIBM66473.2025.11357168","author":"Luo","year":"2025"},{"key":"2026100900062172500_vbag268-B28","doi-asserted-by":"publisher","first-page":"eadh7699","DOI":"10.1126\/science.adh7699","article-title":"Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens","volume":"380","author":"Morris","year":"2023","journal-title":"Science"},{"key":"2026100900062172500_vbag268-B29","doi-asserted-by":"publisher","first-page":"eado9336","DOI":"10.1126\/science.ado9336","article-title":"Sequence modeling and design from molecular to genome scale with evo","volume":"386","author":"Nguyen","year":"2024","journal-title":"Science"},{"key":"2026100900062172500_vbag268-B30","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1126\/science.aax4438","article-title":"Exploring genetic interaction manifolds constructed from rich single-cell phenotypes","volume":"365","author":"Norman","year":"2019","journal-title":"Science"},{"key":"2026100900062172500_vbag268-B31","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/s41576-022-00532-2","article-title":"Obtaining genetics insights from deep learning via explainable artificial intelligence","volume":"24","author":"Novakovsky","year":"2023","journal-title":"Nat Rev Genet"},{"key":"2026100900062172500_vbag268-B32","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1002\/cpdd.1216","article-title":"Phase 1 clinical trial of PPMX-T003, a novel human monoclonal antibody specific for transferrin receptor 1, to evaluate its safety, pharmacokinetics, and pharmacodynamics","volume":"12","author":"Ogama","year":"2023","journal-title":"Clin Pharmacol Drug Dev"},{"key":"2026100900062172500_vbag268-B33","author":"Ota","year":"2026"},{"key":"2026100900062172500_vbag268-B34","doi-asserted-by":"publisher","first-page":"2559","DOI":"10.1016\/j.cell.2022.05.013","article-title":"Mapping information-rich genotype-phenotype landscapes with genome-scale perturb-seq","volume":"185","author":"Replogle","year":"2022","journal-title":"Cell"},{"key":"2026100900062172500_vbag268-B35","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1038\/s41587-023-01905-6","article-title":"Predicting transcriptional outcomes of novel multigene perturbations with GEARS","volume":"42","author":"Roohani","year":"2024","journal-title":"Nat Biotechnol"},{"key":"2026100900062172500_vbag268-B36","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1016\/j.molcel.2007.06.039","article-title":"Epigenetic regulation of hematopoietic differentiation by gfi-1 and gfi-1b is mediated by the cofactors CoREST and LSD1","volume":"27","author":"Saleque","year":"2007","journal-title":"Mol Cell"},{"key":"2026100900062172500_vbag268-B37","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1126\/science.1247005","article-title":"Genome-scale CRISPR-Cas9 knockout screening in human cells","volume":"343","author":"Shalem","year":"2014","journal-title":"Science"},{"key":"2026100900062172500_vbag268-B38","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A next generation connectivity map: l 1000 platform and the first 1,000,000 profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"2026100900062172500_vbag268-B39","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/s41586-023-06139-9","article-title":"Transfer learning enables predictions in network biology","volume":"618","author":"Theodoris","year":"2023","journal-title":"Nature"},{"key":"2026100900062172500_vbag268-B40","first-page":"5998","article-title":"Attention is all you need","volume":"30","author":"Vaswani","year":"2017","journal-title":"Adv Neural Inf Process Syst"},{"key":"2026100900062172500_vbag268-B41","doi-asserted-by":"publisher","first-page":"11","DOI":"10.18653\/v1\/D19-1002","author":"Wiegreffe","year":"2019"},{"key":"2026100900062172500_vbag268-B42","doi-asserted-by":"publisher","author":"Zhao","year":"2025","DOI":"10.48550\/arXiv.2504.13049"}],"container-title":["Bioinformatics Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformaticsadvances\/advance-article-pdf\/doi\/10.1093\/bioadv\/vbag268\/71032744\/vbag268.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformaticsadvances\/article-pdf\/6\/1\/vbag268\/71032744\/vbag268.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformaticsadvances\/article-pdf\/6\/1\/vbag268\/71032744\/vbag268.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:06:30Z","timestamp":1791518790000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformaticsadvances\/article\/doi\/10.1093\/bioadv\/vbag268\/8790609"}},"subtitle":[],"editor":[{"given":"Guoqiang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,7]]}},"URL":"https:\/\/doi.org\/10.1093\/bioadv\/vbag268","relation":{},"ISSN":["2635-0041"],"issn-type":[{"value":"2635-0041","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"vbag268"}}