@article{3fd76663e6c247849937307473dba027,
title = "Cell-specific cis-regulatory elements and mechanisms of non-coding genetic disease in human retina and retinal organoids",
abstract = "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.",
keywords = "MIR-9, cis-regulatory element, development, enhancer, macular telangiectasia type 2, neurogenesis, retina, retinal organoid, single-cell ATAC-seq, single-cell RNA-seq",
author = "Thomas, {Eric D.} and Timms, {Andrew E.} and Sarah Giles and Sarah Harkins-Perry and Pin Lyu and Thanh Hoang and Jiang Qian and Jackson, {Victoria E.} and Melanie Bahlo and Seth Blackshaw and Martin Friedlander and Kevin Eade and Cherry, {Timothy J.}",
note = "Funding Information: We would like to thank all members of the Cherry Lab, James T. Bennett, and the Lowy Medical Research Center (specifically Mari Gantner, Lea Scheppke, and Mike Dorrell), as well as the LMRI Board of Scientific Governors, for discussions about the project. Kimberly A. Aldinger and Thomas Vierbuchen provided independent feedback on this manuscript. We would also like to thank the Lowy family for their funding support of the MacTel Project and Sang Sim, Megan Cook, Marti Lynn Moon, and Jessica Orozoco for administrative assistance. This work was supported by grants from the NIH National Eye Institute ( R01EY028584 to T.J.C., R01EY020560 and U01EY027267 to S.B., R01EY029548 and P30EY001765 to J.Q.) and from the Brotman Baty Institute to T.J.C., an NIH T32 Grant, Experimental Pathology of Cardiovascular Disease Training grant HL007312 to E.D.T., and the Lowy Medical Research Institute to T.J.C. GWAS re-analysis was supported by the Australian Government National Health and Medical Research Council (NHMRC) Investigator Grant ( 1195236 ) to M.B. Additional funding to M.B. was provided by the Australian Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program . The Birth Defects Research Laboratory at the University of Washington and Lion{\textquoteright}s VisionGift of Portland, Oregon provided tissue samples. Lastly, we would like to acknowledge the tissue donors who made this study possible. Funding Information: We would like to thank all members of the Cherry Lab, James T. Bennett, and the Lowy Medical Research Center (specifically Mari Gantner, Lea Scheppke, and Mike Dorrell), as well as the LMRI Board of Scientific Governors, for discussions about the project. Kimberly A. Aldinger and Thomas Vierbuchen provided independent feedback on this manuscript. We would also like to thank the Lowy family for their funding support of the MacTel Project and Sang Sim, Megan Cook, Marti Lynn Moon, and Jessica Orozoco for administrative assistance. This work was supported by grants from the NIH National Eye Institute (R01EY028584 to T.J.C. R01EY020560 and U01EY027267 to S.B. R01EY029548 and P30EY001765 to J.Q.) and from the Brotman Baty Institute to T.J.C. an NIH T32 Grant, Experimental Pathology of Cardiovascular Disease Training grant HL007312 to E.D.T. and the Lowy Medical Research Institute to T.J.C. GWAS re-analysis was supported by the Australian Government National Health and Medical Research Council (NHMRC) Investigator Grant (1195236) to M.B. Additional funding to M.B. was provided by the Australian Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program. The Birth Defects Research Laboratory at the University of Washington and Lion's VisionGift of Portland, Oregon provided tissue samples. Lastly, we would like to acknowledge the tissue donors who made this study possible. E.D.T. A.E.T. S.H.-P. S.G. K.E. and T.J.C. designed and performed experiments and analyses associated with the manuscript. E.D.T. and A.E.T. guided bioinformatic analysis with A.E.T. serving as senior bioinformatician. P.L. T.H. J.Q. and S.B. generated mouse data and assisted with cross-species analyses. V.E.J. and M.B. assisted with human GWAS analyses. Study design was conceptualized by E.D.T. A.E.T. K.E. and T.J.C. E.D.T. and T.J.C. wrote the paper with input from all co-authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = mar,
day = "28",
doi = "10.1016/j.devcel.2022.02.018",
language = "English (US)",
volume = "57",
pages = "820--836.e6",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "6",
}