Abstract
Purpose :
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. However, the cellular complexity of the human brain has largely precluded the identification of functional regulatory variation within the human CNS.
Methods :
We took advantage of the retina, a well-characterized region of the CNS with reduced cellular heterogeneity, to establish a roadmap for characterizing regulatory variation in the human CNS, utilizing epigenomic (ATAC-Seq and ChIP-Seq) and single-cell-RNA-seq methods.
Results :
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, retinal pigment epithelium/choroid) reveals features of regulatory element evolution that shape tissue-specific gene expression programs and define the regulatory elements with the potential to contribute to mendelian and complex disorders of human vision.
Conclusions :
Our comprehensive analysis of transcription factor binding and cis-regulatory elements in these human tissues elucidates the mechanisms of gene regulation necessary for retinal development and function. The results of this study will be broadly useful for identification of non-coding variants that may contribute to inherited or sporatic visual disorders. Our approach also provides a roadmap for how other tissues of visual system can be analyzed to address the contribution of non-coding genetic variation a wider array of pathological conditions.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.