Cell-specific cis-regulatory elements and mechanisms of non-coding genetic disease in human retina and retinal organoids

Eric D. Thomas, Andrew E. Timms, Sarah Giles, Sarah Harkins-Perry, Pin Lyu, Thanh Hoang, Jiang Qian, Victoria E. Jackson, Melanie Bahlo, Seth Blackshaw, Martin Friedlander, Kevin Eade, Timothy J. Cherry

Research output: Contribution to journalArticlepeer-review


Cis-regulatory elements (CREs) play a critical role in the development and disease-states of all human cell types. In the retina, CREs have been implicated in several inherited disorders. To better characterize human retinal CREs, we performed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) and single-nucleus RNA sequencing (snRNA-seq) on the developing and adult human retina and on induced pluripotent stem cell (iPSC)-derived retinal organoids. These analyses identified developmentally dynamic, cell-class-specific CREs, enriched transcription-factor-binding motifs, and putative target genes. CREs in the retina and organoids are highly correlated at the single-cell level, and this supports the use of organoids as a model for studying disease-associated CREs. As a proof of concept, we disrupted a disease-associated CRE at 5q14.3, confirming its principal target gene as the miR-9-2 primary transcript and demonstrating its role in neurogenesis and gene regulation in mature glia. This study provides a resource for characterizing human retinal CREs and showcases organoids as a model to study the function of CREs that influence development and disease.

Original languageEnglish (US)
Pages (from-to)820-836.e6
JournalDevelopmental Cell
Issue number6
StatePublished - Mar 28 2022


  • MIR-9
  • cis-regulatory element
  • development
  • enhancer
  • macular telangiectasia type 2
  • neurogenesis
  • retina
  • retinal organoid
  • single-cell ATAC-seq
  • single-cell RNA-seq

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Molecular Biology
  • Cell Biology
  • Developmental Biology


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