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We present CREMA, a framework that recovers the full cis-regulatory circuitry by modeling gene expression and chromatin activity in individual cells without peak-calling or cell type labeling constraints. We demonstrate that CREMA overcomes the limitations of existing methods that fail to identify about half of functional regulatory elements which are outside the called chromatin \u2018peaks\u2019. These circuit sites outside called peaks are shown to be important cell type specific functional regulatory loci, sufficient to distinguish individual cell types. Analysis of mouse pituitary data identifies a Gata2-circuit for the gonadotrope-enriched disease-associated Pcsk1 gene, which is experimentally validated by reduced gonadotrope expression in a gonadotrope conditional Gata2-knockout model. We present a web accessible human immune cell regulatory circuit resource, and provide CREMA as an R package.<\/jats:p>","DOI":"10.1093\/nar\/gkad1166","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T18:58:23Z","timestamp":1701111503000},"page":"572-582","source":"Crossref","is-referenced-by-count":9,"title":["Peak-agnostic high-resolution cis-regulatory circuitry mapping using single cell multiome data"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6917-8195","authenticated-orcid":false,"given":"Zidong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai (ISMMS) , New York , NY , USA"},{"name":"Lewis-Sigler Institute for Integrative Genomics, Princeton University , Princeton , NJ , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederique","family":"Ruf-Zamojski","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai (ISMMS) , New York , NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Zamojski","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai (ISMMS) , New York , NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel\u00a0J","family":"Bernard","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University , Montreal , QC H3G 1Y6 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Computational Biology, Flatiron Institute , Simons Foundation, New York , NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga\u00a0G","family":"Troyanskaya","sequence":"additional","affiliation":[{"name":"Lewis-Sigler Institute for Integrative Genomics, Princeton University , Princeton , NJ , USA"},{"name":"Center for Computational Biology, Flatiron Institute , Simons Foundation, New York , NY , USA"},{"name":"Department of Computer Science, Princeton University , Princeton , NJ , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart\u00a0C","family":"Sealfon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai (ISMMS) , New York , NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,12]]},"reference":[{"key":"2024012516171025400_B1","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1126\/science.1171347","article-title":"Transcriptional regulatory circuits: predicting numbers from alphabets","volume":"325","author":"Kim","year":"2009","journal-title":"Science"},{"key":"2024012516171025400_B2","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.cell.2020.09.056","article-title":"Chromatin potential identified by shared single-cell profiling of RNA and Chromatin","volume":"183","author":"Ma","year":"2020","journal-title":"Cell"},{"key":"2024012516171025400_B3","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/s41587-019-0290-0","article-title":"High-throughput sequencing of the transcriptome and chromatin accessibility in the same cell","volume":"37","author":"Chen","year":"2019","journal-title":"Nat. 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