3D epigenomic landscape of the human retinal pigment epithelium

The retinal pigment epithelium (RPE) is crucial for visual function, and its dysfunction contributes to retinal diseases such as age-related macular degeneration. Despite the translational potential of iPSC-derived RPE (iPSC-RPE) in cell replacement therapy, the functional visual gains achieved to date are modest. A key challenge is that the molecular and epigenomic signatures underlying functional RPE are yet to be fully elucidated. By integrating multiomics data, we systematically benchmarked the 3D epigenomic landscapes of primary human RPE (hRPE), iPSC-RPE, and the immortalized ARPE-19 cell line. Our analysis reveals that iPSC-RPE exhibits a mixed molecular state. iPSC-RPE recapitulates hRPE-like transcription and chromatin looping, but its histone modification states remain incompletely matured, and its chromatin accessibility and higher-order chromatin organization do not fully converge to hRPE. Furthermore, we found that hRPE exhibits strong extracellular matrix (ECM) organization driven by enhancer-mediated long-range chromatin interactions and enriched RUNX1 motifs, while iPSC-RPE retains key developmental-related transcriptional signatures, marked by factors such as HAND1, OTX2, and PAX6. These findings establish a multiomics benchmark for RPE maturity, pinpoint key regulatory nodes like ECM organization and RUNX1 for therapeutic targeting, and provide a roadmap for optimizing differentiation protocols and scaffold design in retinal regenerative medicine.