{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:52Z","timestamp":1792790392495,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,16]]},"group-title":"Bioinformatics","reference-count":104,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alzheimer\u2019s Association Research Grant","award":["R01AG071683"],"award-info":[{"award-number":["R01AG071683"]}],"id":[{"id":"https:\/\/ror.org\/0375f4d26","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Cure Alzheimer\u2019s Fund","id":[{"id":"https:\/\/ror.org\/05ewr7t48","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Aging of the National Institutes of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,16]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>Single-nucleus multiome assays jointly profile gene expression and chromatin accessibility, yet their analysis typically requires bespoke chaining of modality-specific tools, creating barriers to reproducibility, scalability, and regulatory interpretation. We present FORGE (Flow Orchestrated Regulatory Genomics Engine), a configurable workflow that automates standalone snRNA-seq and snATAC-seq analysis, integrates the pair through complementary linear and nonlinear latent-variable models, and carries them through regulatory-network inference and differential testing. We evaluated FORGE on four human and mouse datasets spanning blood, brain, and kidney and two multiome chemistries, including a twelve-sample CRND8 Alzheimer\u2019s disease cohort. We report cross-modal agreement alongside missing-modality reconstruction and an accounting of computational cost. In the Alzheimer\u2019s cohort, FORGE nominated a glial Mef2c-associated program defensible across expression, co-accessibility, footprinting, and eRegulon evidence. In human PBMC, FORGE\u2019s layered evidence models also provide nuanced interpretations that largely corroborate previously published regulatory links while also proposing an additional CD83 myeloid module.<\/jats:p>\n                <jats:sec>\n                  <jats:title>MOTIVATION<\/jats:title>\n                  <jats:p>Single-nucleus resolution multiome (snMultiome) assays concurrently profile gene expression and chromatin accessibility in the same nucleus. Yet regulatory inference from such analyses are difficult to scale, audit, and reproduce; moreover, as a field, snMultiomics and its\u2019 toolset remains far from standardized. To address these challenges we developed FORGE, a configureable Nextflow workflow that carries paired data from raw counts and fragments through regulatory network inference with a comprehensive differential testing suite. Execution is containerized, tracks provenance, robust to interruption, optimized for cluster-based compute environments, and allows for nuanced customization of specific processes.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.10.750690","type":"posted-content","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:30:17Z","timestamp":1789583417000},"source":"Crossref","is-referenced-by-count":0,"title":["Flow Orchestrated Regulatory Genomics Engine (FORGE): A Configurable Nextflow Pipeline for End-to-End snMultiome Analysis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2336-3854","authenticated-orcid":false,"given":"Luis E","family":"Solano","sequence":"first","affiliation":[{"name":"Mathematical, Computational, and Systems Biology (MCSB) Program, UC Irvine, Irvine, USA"},{"name":"Center for Complex Biological Systems, Biology, UC Irvine, Irvine, USA"},{"name":"Department of Neurobiology and Behavior, UC Irvine, Irvine, USA"},{"name":"Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, Irvine, CA, USA"},{"name":"Department of Systems Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7797-620X","authenticated-orcid":false,"given":"Negin","family":"Rahimzadeh","sequence":"additional","affiliation":[{"name":"Mathematical, Computational, and Systems Biology (MCSB) Program, UC Irvine, Irvine, USA"},{"name":"Center for Complex Biological Systems, Biology, UC Irvine, Irvine, USA"},{"name":"Department of Neurobiology and Behavior, UC Irvine, Irvine, USA"},{"name":"Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, Irvine, CA, USA"},{"name":"Department of Systems Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2844-5816","authenticated-orcid":false,"given":"Zechuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, UC Irvine, Irvine, USA"},{"name":"Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, Irvine, CA, USA"},{"name":"Department of Systems Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3762-2746","authenticated-orcid":false,"given":"Vivek","family":"Swarup","sequence":"additional","affiliation":[{"name":"Mathematical, Computational, and Systems Biology (MCSB) Program, UC Irvine, Irvine, USA"},{"name":"Center for Complex Biological Systems, Biology, UC Irvine, Irvine, USA"},{"name":"Department of Neurobiology and Behavior, UC Irvine, Irvine, USA"},{"name":"Institute for Memory Impairments and Neurological Disorders (MIND), University of California, Irvine, Irvine, CA, USA"},{"name":"Department of Systems Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026091921351483000_2026.09.10.750690v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3820"},{"key":"2026091921351483000_2026.09.10.750690v1.2","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.29032.1"},{"key":"2026091921351483000_2026.09.10.750690v1.3","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.10679327"},{"key":"2026091921351483000_2026.09.10.750690v1.4","unstructured":"CNIO-BU. bollito: Bioinformatics tools [Internet]. 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