Single-cell analysis of the epigenome and 3D chromatin architecture in the human retina
Most genetic risk variants linked to ocular diseases are nonprotein coding and presumably contribute to disease through dysregulation of gene expression; however, understanding their mechanisms has been impeded by incomplete annotation of transcriptional regulatory elements across retinal cell types. To address this, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome, and three-dimensional (3D) chromatin architecture in human retina, macula, and retinal pigment epithelium/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 retinal cell types. Comparative analysis of chromatin landscapes between human and mouse retina cells further revealed both evolutionarily conserved and divergent retinal gene-regulatory programs. Leveraging the advancements in deep-learning techniques, we developed sequence-based predictors to interpret noncoding risk variants of retinal diseases. Our study establishes retina-wide, single-cell transcriptome, epigenome, and 3D genome atlases and provides a resource for studying the gene regulatory programs of the human retina and ocular diseases.
Authors
- Justin Buchanan (ORCID: https://orcid.org/0000-0001-5904-222X)
- Sebastian Preißl (ORCID: https://orcid.org/0000-0001-8971-5616)
- Yang Xie (ORCID: https://orcid.org/0000-0002-7453-6786)
- Nathan R. Zemke (ORCID: https://orcid.org/0000-0002-6326-5925)
- Kelsey Dang
- Pooja Biswas (ORCID: https://orcid.org/0000-0002-8545-9296)
- Joseph R. Ecker (ORCID: https://orcid.org/0000-0001-5799-5895)
- Seo Yeon Lee (ORCID: https://orcid.org/0000-0003-2585-7863)
- Zane A. Gibbs (ORCID: https://orcid.org/0000-0003-0294-1878)
- Allen Wang (ORCID: https://orcid.org/0000-0001-9870-7888)
- Matteo D’Antonio (ORCID: https://orcid.org/0000-0001-5844-6433)
- Bing Ren (ORCID: https://orcid.org/0000-0002-5435-1127)
- Daofeng Li (ORCID: https://orcid.org/0000-0001-7492-3703)
- Radha Ayyagari (ORCID: https://orcid.org/0000-0002-6804-7740)
- Kelly A. Frazer (ORCID: https://orcid.org/0000-0002-6060-8902)
- Pik Ki Lau
- Qian Yang (ORCID: https://orcid.org/0000-0002-2405-2396)
- Lin Lin (ORCID: https://orcid.org/0000-0002-7464-1172)
- Ting Wang (ORCID: https://orcid.org/0000-0002-6800-242X)
- Kangli Wang (ORCID: https://orcid.org/0009-0008-0699-0101)
- Keyi Dong
- Ying Yuan (ORCID: https://orcid.org/0000-0002-5881-6956)
- Weronika M. Bartosik
- Chad Seng
- Ryan Lancione
- Yue Wu (ORCID: https://orcid.org/0000-0002-9230-1673)
- Bing Yang (ORCID: https://orcid.org/0009-0004-8590-5358)
Institutions
- Salk Institute for Biological Studies (US)
- University of Graz (AT)
- University of Freiburg (DE)
- Washington University in St. Louis (US)
- UC San Diego Health System (US)
- University of California San Diego (US)
- La Jolla Institute For Molecular Medicine (US)
- Smith-Kettlewell Eye Research Institute (US)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1126/sciadv.adv9162
- Citations
- 5
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 4.05
Funders
- Foundation Fighting Blindness
- National Institutes of Health