{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:21Z","timestamp":1792790421207,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Bioinformatics","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01HL125877, R01HL160927, R01HL174922, and R01HL179184"],"award-info":[{"award-number":["R01HL125877, R01HL160927, R01HL174922, and R01HL179184"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"American Heart Association","award":["26POST1552066"],"award-info":[{"award-number":["26POST1552066"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Matched epigenomic profiling remains scarce in human heart failure, limiting regulatory interpretation of single-nucleus ribonucleic acid (RNA) sequencing data. We developed CardioChrom, a cardiac-specialized framework that reconstructs chromatin accessibility, histone H3 lysine 27 acetylation (H3K27ac), and histone H3 lysine 27 trimethylation (H3K27me3) from single-nucleus RNA profiles.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>CardioChrom was developed using same-nucleus human heart datasets jointly measuring RNA with chromatin accessibility by assay for transposase-accessible chromatin (ATAC), H3K27ac, or H3K27me3, with donor-separated development and leave-one-cell-type-out testing. Frozen models were evaluated in 10-donor and 23-sample external human heart cohorts. Histone reconstruction was benchmarked against measured profiles and a Transformer. The models were then applied without refitting to an RNA-only cohort of 43 donors with heart failure with preserved ejection fraction (HFpEF).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Across unseen cardiac cell types, CardioChrom increased area under the precision\u2013 recall curve by 0.0109 relative to within-cell-type RNA shuffling in 11 of 12 cell types and increased area under the receiver operating characteristic curve by 0.0179 in all 12.<\/jats:p>\n                  <jats:p>CardioChrom exceeded controls in both external cohorts and matched or exceeded the Transformer across 6 prespecified histone metrics. In HFpEF, 3,581 donor-level pathway\u2013layer associations met global false discovery rate, sex-adjustment, and leave-one-donor-out robustness criteria. Endothelial cells showed prominent reconstructed histone-associated changes involving coagulation, inflammation, hypoxia, and profibrotic signaling. Von Willebrand factor expression and its reconstructed regulatory states were consistently reduced, and all 6 linked candidate cis-regulatory elements were classified as repressed. Motif-supported TF\u2013cCRE\u2013gene hypotheses were generated in endothelial cells and fibroblasts.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>CardioChrom extends RNA-only human heart failure cohorts toward cell-type-resolved virtual epigenomic and regulatory analysis while distinguishing predictions from direct measurements.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Clinical Perspective<\/jats:title>\n                  <jats:sec>\n                    <jats:title>What Is New?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>CardioChrom is, to our knowledge, the first cardiac-specialized virtual epigenome framework to integrate same-nucleus human heart RNA\u2013ATAC and RNA\u2013histone reference data to reconstruct chromatin accessibility, H3K27ac, and H3K27me3 states from single-nucleus RNA profiles.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>The framework was tested beyond its training setting, including unseen donors, leave-one-cell-type-out evaluation, and independent human heart cohorts, and consistently exceeded simple RNA-shuffled or peak-frequency baselines while remaining competitive with or superior to Transformer-based comparators.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>What Are the Clinical Implications?<\/jats:title>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Many heart-failure cohorts contain transcriptomic data without matched epigenomic measurements. CardioChrom provides a way to extend these RNA-only datasets toward cell-type-resolved regulatory-state analysis without requiring additional tissue or multimodal assays.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>In an independent RNA-only HFpEF cohort, CardioChrom identified prominent endothelial regulatory remodeling involving Coagulation, IL6\/JAK\/STAT3, TNF\u03b1\/NF\u03baB, Hypoxia, and TGF-\u03b2\/EMT and generated TF\u2013cCRE\u2013gene hypotheses that can be prioritized for experimental validation.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.18.752723","type":"posted-content","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:45:11Z","timestamp":1790307911000},"source":"Crossref","is-referenced-by-count":0,"title":["CardioChrom Reconstructs the Human Cardiac Virtual Epigenome from Single-Nucleus Transcriptomes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5420-3415","authenticated-orcid":false,"given":"Hongbiao","family":"Huang","sequence":"first","affiliation":[{"name":"Phoenix Children\u2019s Research Institute, Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"},{"name":"Translational Cardiovascular Research Center, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Hui","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Research Institute, Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"},{"name":"Translational Cardiovascular Research Center, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjian","family":"Li","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Research Institute, Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"},{"name":"Translational Cardiovascular Research Center, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Abdelbaset-Ismail","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Research Institute, Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"},{"name":"Translational Cardiovascular Research Center, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Research Institute, Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"},{"name":"Translational Cardiovascular Research Center, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suchen","family":"Yadav","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Research Institute, Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"},{"name":"Translational Cardiovascular Research Center, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Tan","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Research Institute, Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"},{"name":"Translational Cardiovascular Research Center, University of Arizona College of Medicine \u2013 Phoenix, Phoenix, AZ, USA"},{"name":"Pediatric Research Institute, Departments of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA"},{"name":"Wendy Novak Diabetes Institute, Norton Children\u2019s Hospital, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092906551371000_2026.09.18.752723v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2797-4"},{"key":"2026092906551371000_2026.09.18.752723v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04817-8"},{"key":"2026092906551371000_2026.09.18.752723v1.3","doi-asserted-by":"crossref","unstructured":"Xie Y , Tucciarone L , Farah EN , Chang L , Yang \u01ea , Shankar TS , et al. 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