Gent University

Human adult neural retina contains seven major cell classes and is bordered by the retinal pigment epithelium (RPE) and choroid layer. Cis-regulatory elements (CREs) in human adult and developing retina have been mapped using bulk and single-cell transcriptomics and epigenomics, providing insight into gene regulation and contributing to non-coding variant interpretation in inherited retinal diseases (IRD). IRD represent a major cause of early-onset blindness in over two million people worldwide. Yet, a map of the 3D conformation of the genome in human retina, an important determinant of CRE-target gene specificity, is still lacking. Given the complex multi-omics signatures, we hypothesize that regional and cell-class-specific 3D topologies exist in human retina.

Our main goal is to investigate 3D genome architecture in adult human retina to confidently link CREs to retinal target genes. Specifically, we aim to: (1) establish a regional and (2) cell-class-specific 3D genome map of adult human retina using state-of-the-art (Hi-C) and novel C-technologies (Probe-C); (3) functionally annotate retinal 3D landscapes and create an integrated regulatory database for human retina; (4) determine effects of structural variants (SVs) in IRD using Hi-C and retinal 3D topologies.

Overall, this study has tremendous potential to unlock 3D genome architecture in human retina and to uncover the role of SVs with an impact on the 3D genome as a cause of missing heritability in IRD and as novel targets for intervention.