An Integrated Multi-omics Single Cell Atlas of the Human RPE and Choroid

Area of Science:

• Ophthalmology
• Genomics
• Cell Biology

Background:

• The retinal pigment epithelium (RPE) and choroid are crucial for outer retina health.
• Dysfunction in these tissues contributes to various inherited and complex eye diseases.

Purpose of the Study:

• To build an integrated multi-omics reference atlas of the RPE and choroid.
• To characterize cellular, transcriptomic, and epigenomic heterogeneity and dynamics.
• To identify age-related changes and disease associations.

Main Methods:

• Assembled a large-scale dataset of single-cell/nucleus transcriptomes and snATAC-seq profiles.
• Included data from 102 ancestrally diverse donors across a wide age range (0-99 years).
• Analyzed macular and peripheral tissue samples.

Main Results:

• Resolved 48 distinct cell types/states and 448,567 open chromatin regions.
• Identified five RPE subpopulations, two stress/senescence states, and detailed choroidal stromal heterogeneity.
• Revealed age-associated depletion of specific cell types (melanocytes, PI16+ fibroblasts) and shifts in RPE distribution.
• Uncovered shared inflammatory pathways and distinct cell-type-specific aging signatures.
• Detected significant age-associated epigenetic changes in the macula, with AP-1/bZIP transcription factors being dominant.
• Linked genetic variants (LIPG, COL4A3) to age-related macular degeneration (AMD) pathogenesis.

Conclusions:

• The multi-omics atlas provides a valuable reference for RPE/choroid biology.
• It serves as a discovery engine, translating genetic risk into cellular mechanisms for ocular diseases like AMD.
• This work lays the foundation for understanding RPE/choroid function in health and disease.