Mapping the cis-regulatory architecture of the human retina reveals noncoding genetic variation in disease

Regulation of gene expression is critical for all complex biological processes including vision. Mutations within cis-regulatory elements (CREs) can disrupt gene expression and contribute to human diseases. However, it is challenging to screen for mutations within CREs that affect vision because the genomic locations and mechanisms of action of these elements are largely unknown. Here, we take advantage of advances in epigenomic and transcriptomic profiling techniques to identify and characterize CREs in three regions of the human eye commonly affected in visual disorders. Our data identify shared and unique CREs in each region, reveal the combinatorial binding of TFs, and provide a resource for understanding the role of noncoding genetic variation in visual disorders.

The interplay of transcription factors and cis-regulatory elements (CREs) orchestrates the dynamic and diverse genetic programs that assemble the human central nervous system (CNS) during development and maintain its function throughout life. Genetic variation within CREs plays a central role in phenotypic variation in complex traits including the risk of developing disease. We took advantage of the retina, a well-characterized region of the CNS known to be affected by pathogenic variants in CREs, to establish a roadmap for characterizing regulatory variation in the human CNS. This comprehensive analysis of tissue-specific regulatory elements, transcription factor binding, and gene expression programs in three regions of the human visual system (retina, macula, and retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and defines regulatory elements with the potential to contribute to Mendelian and complex disorders of human vision.