{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T10:05:10Z","timestamp":1789639510334,"version":"4.0.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Plant Sci."],"abstract":"<jats:p>Sequence-to-function (seq2func) models predict molecular regulatory outputs from DNA sequence and can prioritize non-coding variants, annotate cis-regulatory elements (CREs), and design regulatory sequences. Although accuracy has improved, most models are trained and evaluated on observational data from one or a few reference genomes. Their performance may therefore not translate to natural haplotypes, structural variants, tissues, developmental stages, environments, or species. These limitations are especially important in plants, where pan-genomic diversity, transposable elements, polyploidy, long-range regulation, and genotype-by-environment interactions shape regulatory landscapes. This Mini Review summarizes seq2func modelling in plant regulatory genomics, discusses plant-specific challenges and the complementary value of observational and perturbation assays, and proposes evaluation frameworks based on biologically meaningful distribution shifts. We further outline how pan-genomes, multi-omics, genome editing, reporter assays, active learning, and continual learning could support closed-loop experimental\u2013computational systems. Progress should be judged not only by reference-genome accuracy, but by calibrated and experimentally validated generalization across plant diversity.<\/jats:p>","DOI":"10.3389\/fpls.2026.1968878","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:48:37Z","timestamp":1789638517000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From reference-genome prediction to causal generalization: sequence-to-function models for plant regulatory genomics"],"prefix":"10.3389","volume":"17","author":[{"given":"Mingfang","family":"Zhan","sequence":"first","affiliation":[{"name":"College of Life Sciences, Wuchang University of Technology","place":["Wuhan, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruigang","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Landscape and Ecological Engineering, Hebei University of Engineering","place":["Handan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6200","DOI":"10.1038\/s41467-026-75527-2","article-title":"Context-aware sequence-to-function model of human gene regulation","volume":"17","author":"Aksu","year":"2026","journal-title":"Nat. Commun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/nature10241","article-title":"A polycomb-based switch underlying quantitative epigenetic memory","volume":"476","author":"Angel","year":"2011","journal-title":"Nature"},{"key":"B3","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":"B4","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1105\/tpc.104.025627","article-title":"Evolution of DNA sequence nonhomologies among maize inbreds","volume":"17","author":"Brunner","year":"2005","journal-title":"Plant Cell"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1038\/nmeth.2688","article-title":"Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position","volume":"10","author":"Buenrostro","year":"2013","journal-title":"Nat. Methods"},{"key":"B6","doi-asserted-by":"publisher","first-page":"101238","DOI":"10.1016\/j.xplc.2024.101238","article-title":"Gap-free genome assemblies of two Pyrus bretschneideri cultivars and GWAS analyses identify a CCCH zinc finger protein as a key regulator of stone cell formation in pear fruit","volume":"6","author":"Cao","year":"2025","journal-title":"Plant Commun."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.indcrop.2026.124139","article-title":"Overexpression of Camellia oleifera ColERF04 accelerates flowering in transgenic Arabidopsis","volume":"251","author":"Cao","year":"2026","journal-title":"Ind. Crops Prod."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.indcrop.2026.124249","article-title":"Integrative genomics of Oil-Camellia: From multi-omics dissection of key traits to mechanism-informed molecular breeding","volume":"251","author":"Cao","year":"2026","journal-title":"Ind. Crops Prod."},{"key":"B9","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/nrg.2016.139","article-title":"Regulatory activities of transposable elements: from conflicts to benefits","volume":"18","author":"Chuong","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1101\/gr.224964.117","article-title":"Deep learning of the regulatory grammar of yeast 5\u2032 untranslated regions from 500,000 random sequences","volume":"27","author":"Cuperus","year":"2017","journal-title":"Genome Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s41592-024-02523-z","article-title":"Nucleotide transformer: building and evaluating robust foundation models for human genomics","volume":"22","author":"Dalla-Torre","year":"2025","journal-title":"Nat. Methods"},{"key":"B12","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.pbi.2019.12.005","article-title":"Plant pangenomics: approaches, applications and advancements","volume":"54","author":"Danilevicz","year":"2020","journal-title":"Curr. Opin. Plant Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1038\/s41588-024-01830-7","article-title":"Unlocking plant genetics with telomere-to-telomere genome assemblies","volume":"56","author":"Garg","year":"2024","journal-title":"Nat. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1038\/s41586-024-08070-z","article-title":"Machine-guided design of cell-type-targeting cis-regulatory elements","volume":"634","author":"Gosai","year":"2024","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1126\/science.abg5289","article-title":"De novo assembly, annotation, and comparative analysis of 26 diverse maize genomes","volume":"373","author":"Hufford","year":"2021","journal-title":"Science"},{"key":"B16","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.hpj.2024.02.002","article-title":"Rosaceae phylogenomic studies provide insights into the evolution of new genes","volume":"11","author":"Jiang","year":"2025","journal-title":"Hortic. Plant J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1105\/tpc.20.00155","article-title":"Identification of plant enhancers and their constituent elements by STARR-seq in tobacco leaves","volume":"32","author":"Jores","year":"2020","journal-title":"Plant Cell"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1038\/s41467-019-09982-5","article-title":"CUT&Tag for efficient epigenomic profiling of small samples and single cells","volume":"10","author":"Kaya-Okur","year":"2019","journal-title":"Nat. Commun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1101\/gr.200535.115","article-title":"Basset: learning the regulatory code of the accessible genome with deep convolutional neural networks","volume":"26","author":"Kelley","year":"2016","journal-title":"Genome Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3521","DOI":"10.1073\/pnas.1611835114","article-title":"Overcoming catastrophic forgetting in neural networks","volume":"114","author":"Kirkpatrick","year":"2017","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"117037","DOI":"10.1016\/j.celrep.2026.117037","article-title":"Haplotype-resolved genome of hexaploid Solanum nigrum: Insights into origin, evolution, and steroidal glycoalkaloid biosynthesis","volume":"45","author":"Kong","year":"2026","journal-title":"Cell Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"101436","DOI":"10.1016\/j.xplc.2025.101436","article-title":"The haplotype-resolved genome assembly of the hexaploid kiwifruit Actinidia deliciosa reveals its hybrid origin and polysomic inheritance","volume":"6","author":"Li","year":"2025","journal-title":"Plant Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"100384","DOI":"10.1016\/j.crmeth.2022.100384","article-title":"Applications of deep learning in understanding gene regulation","volume":"3","author":"Li","year":"2023","journal-title":"Cell Rep. Methods"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.48130\/forres-0025-0017","article-title":"Assessing the accuracy of forest above-ground biomass and carbon storage estimation by meta-analysis based close-range remote sensing","volume":"5","author":"Liu","year":"2025","journal-title":"Forestry Res."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.48130\/forres-0024-0016","article-title":"A nearly gapless, highly contiguous reference genome for a doubled haploid line of Populus ussuriensis, enabling advanced genomic studies","volume":"4","author":"Liu","year":"2024","journal-title":"Forestry Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1038\/s41586-020-03127-1","article-title":"Genomic mechanisms of climate adaptation in polyploid bioenergy switchgrass","volume":"590","author":"Lovell","year":"2021","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2512889122","article-title":"Decoding nature\u2019s grammar with DNA language models","volume":"122","author":"Morrell","year":"2025","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.48130\/forres-0025-0014","article-title":"Gene regulatory network prediction using machine learning, deep learning, and hybrid approaches","volume":"5","author":"Mummadi","year":"2025","journal-title":"Forestry Res."},{"key":"B29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/978-981-97-7744-0_2","article-title":"Genomics, pan-genomics, and super pan-genomics of major oilseed crops","volume-title":"Breeding Climate Resilient and Future Ready Oilseed Crops","author":"Naik","year":"2025"},{"key":"B31a","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41746-025-02311-9","article-title":"Leveraging large scale deep learning models for diagnosis and visual outcome prediction in retinitis pigmentosa","volume":"9","author":"Nagai","year":"2026","journal-title":"npj Digi Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.neunet.2019.01.012","article-title":"Continual lifelong learning with neural networks: A review","volume":"113","author":"Parisi","year":"2019","journal-title":"Neural Networks"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3488","DOI":"10.1038\/s41467-024-47744-0","article-title":"Deep learning the cis-regulatory code for gene expression in selected model plants","volume":"15","author":"Peleke","year":"2024","journal-title":"Nat. Commun."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar6089","article-title":"The transcriptional landscape of polyploid wheat","volume":"361","author":"Ram\u00edrez-Gonz\u00e1lez","year":"2018","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1038\/s41477-019-0547-0","article-title":"Widespread long-range cis-regulatory elements in the maize genome","volume":"5","author":"Ricci","year":"2019","journal-title":"Nat. Plants"},{"key":"B34","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1016\/j.cell.2017.08.030","article-title":"Engineering quantitative trait variation for crop improvement by genome editing","volume":"171","author":"Rodr\u00edguez-Leal","year":"2017","journal-title":"Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"E7317","DOI":"10.1073\/pnas.1615268113","article-title":"Genetic architecture of nonadditive inheritance in Arabidopsis thaliana hybrids","volume":"113","author":"Seymour","year":"2016","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.molp.2022.12.009","article-title":"Plant pan-genomics and its applications","volume":"16","author":"Shi","year":"2023","journal-title":"Mol. Plant"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.7554\/elife.20777","article-title":"Population scale mapping of transposable element diversity reveals links to gene regulation and epigenomic variation","volume":"5","author":"Stuart","year":"2016","journal-title":"elife"},{"key":"B38","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.tplants.2019.09.004","article-title":"Lessons from domestication: targeting cis-regulatory elements for crop improvement","volume":"21","author":"Swinnen","year":"2016","journal-title":"Trends Plant Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/s41586-020-2961-x","article-title":"Multiple wheat genomes reveal global variation in modern breeding","volume":"588","author":"Walkowiak","year":"2020","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41586-018-0063-9","article-title":"Genomic variation in 3,010 diverse accessions of Asian cultivated rice","volume":"557","author":"Wang","year":"2018","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","first-page":"100985","DOI":"10.1016\/j.xplc.2024.100985","article-title":"DeepCBA: A deep learning framework for gene expression prediction in maize based on DNA sequences and chromatin interactions","volume":"5","author":"Wang","year":"2024","journal-title":"Plant Commun."},{"key":"B42","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/s41576-021-00434-9","article-title":"Navigating the pitfalls of applying machine learning in genomics","volume":"23","author":"Whalen","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"B43","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/nrg3095","article-title":"Cis-regulatory elements: molecular mechanisms and evolutionary processes underlying divergence","volume":"13","author":"Wittkopp","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2950","DOI":"10.1111\/pce.15318","article-title":"MangroveDB: A comprehensive online database for mangroves based on multi\u2010omics data","volume":"48","author":"Xu","year":"2025","journal-title":"Plant Cell Environ."},{"key":"B45","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1146\/annurev.arplant.57.032905.105444","article-title":"Transcriptional regulatory networks in cellular responses and tolerance to dehydration and cold stresses","volume":"57","author":"Yamaguchi-Shinozaki","year":"2006","journal-title":"Annu. Rev. Plant Biol."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2421738122","article-title":"Cross-species modeling of plant genomes at single-nucleotide resolution using a pretrained DNA language model","volume":"122","author":"Zhai","year":"2025","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1038\/nbt.4202","article-title":"Genome editing of upstream open reading frames enables translational control in plants","volume":"36","author":"Zhang","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/nmeth.3547","article-title":"Predicting effects of noncoding variants with deep learning\u2013based sequence model","volume":"12","author":"Zhou","year":"2015","journal-title":"Nat. Methods"}],"container-title":["Frontiers in Plant Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpls.2026.1968878\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:48:38Z","timestamp":1789638518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpls.2026.1968878\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":49,"alternative-id":["10.3389\/fpls.2026.1968878"],"URL":"https:\/\/doi.org\/10.3389\/fpls.2026.1968878","relation":{},"ISSN":["1664-462X"],"issn-type":[{"value":"1664-462X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]},"article-number":"1968878"}}