A single-nucleus multi-omic atlas of gene regulation across 21 adult human tissues
- 1Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142
Abstract
Diverse human cell types establish specialized functions through lineage- and context-specific regulatory programs. Interpreting non-coding genetic risk requires integrated multi-omic reference maps that directly connect regulatory DNA to cellular expression across human tissues. Here we present a single-nucleus multi-omic atlas comprising 459,856 transcriptomic and chromatin accessibility profiles from 21 adult human tissues and four donors, including paired measurements from 160,688 nuclei. The atlas resolves nine cell lineages, 61 broad cell types and 313 subclusters, and identifies 1,085,062 candidate cis-regulatory elements (cCREs), including 161,270 novel elements absent from ENCODE. Regulatory activity was dominated by cell identity but refined by tissue context. Joint profiling enabled 871,177 cCRE-gene associations and revealed lineage-specific regulatory architectures. Cross-tissue accessibility further identified lineage-restricted and constitutively inaccessible chromatin domains, the latter showing preferential hypomethylation across human cancers. Furthermore, we leverage this dataset to train sequence-to-function models to predict chromatin-accessibility effects for 548,656 fine-mapped variants, identifying 18,133 high-effect variants, including 1,120 broadly active variants. Models trained for eight endothelial subtypes further resolve predicted variant effects across vascular beds. Together, this atlas provides a comprehensive cellular and computational framework for interpreting regulatory sequence, context-dependent gene control, and complex trait genetics across the human body.
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BibTeX
@misc{fan2026singlenucleus,
title = {{A single-nucleus multi-omic atlas of gene regulation across 21 adult human tissues}},
author = {K. Fan and A. Sule and A. Guillaumet-Adkins and R. Zhang and T. Yu and Z. Cao and X. Zhang and N. Durand and M. Tellier and L. Domenech and F. Aguet and J. D. Buenrostro and K. G. Ardlie},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754561},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754561v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A single-nucleus multi-omic atlas of gene regulation across 21 adult human tissues
AU - K. Fan
AU - A. Sule
AU - A. Guillaumet-Adkins
AU - R. Zhang
AU - T. Yu
AU - Z. Cao
AU - X. Zhang
AU - N. Durand
AU - M. Tellier
AU - L. Domenech
AU - F. Aguet
AU - J. D. Buenrostro
AU - K. G. Ardlie
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754561
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754561v1
AB - Diverse human cell types establish specialized functions through lineage- and context-specific regulatory programs. Interpreting non-coding genetic risk requires integrated multi-omic reference maps that directly connect regulatory DNA to cellular expression across human tissues. Here we present a single-nucleus multi-omic atlas comprising 459,856 transcriptomic and chromatin accessibility profiles from 21 adult human tissues and four donors, including paired measurements from 160,688 nuclei. The atlas resolves nine cell lineages, 61 broad cell types and 313 subclusters, and identifies 1,085,062 candidate cis-regulatory elements (cCREs), including 161,270 novel elements absent from ENCODE. Regulatory activity was dominated by cell identity but refined by tissue context. Joint profiling enabled 871,177 cCRE-gene associations and revealed lineage-specific regulatory architectures. Cross-tissue accessibility further identified lineage-restricted and constitutively inaccessible chromatin domains, the latter showing preferential hypomethylation across human cancers. Furthermore, we leverage this dataset to train sequence-to-function models to predict chromatin-accessibility effects for 548,656 fine-mapped variants, identifying 18,133 high-effect variants, including 1,120 broadly active variants. Models trained for eight endothelial subtypes further resolve predicted variant effects across vascular beds. Together, this atlas provides a comprehensive cellular and computational framework for interpreting regulatory sequence, context-dependent gene control, and complex trait genetics across the human body.
ER -