{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T23:10:11Z","timestamp":1790291411836,"version":"4.1.0"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T00:00:00Z","timestamp":1706140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NHMRC Program","award":["1150144"],"award-info":[{"award-number":["1150144"]}]},{"name":"NHMRC Program","award":["1132454"],"award-info":[{"award-number":["1132454"]}]},{"DOI":"10.13039\/100012697","name":"Clifford Craig Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012697","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Primary open angle glaucoma (POAG) is a leading cause of blindness globally. Characterized by progressive retinal ganglion cell degeneration, the precise pathogenesis remains unknown. Genome-wide association studies (GWAS) have uncovered many genetic variants associated with elevated intraocular pressure (IOP), one of the key risk factors for POAG. We aimed to identify genetic and morphological variation that can be attributed to trabecular meshwork cell (TMC) dysfunction and raised IOP in POAG.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>62 genes across 55 loci were knocked-out in a primary human TMC line. Each knockout group, including five non-targeting control groups, underwent single-cell RNA-sequencing (scRNA-seq) for differentially-expressed gene (DEG) analysis. Multiplexed fluorescence coupled with CellProfiler image analysis allowed for single-cell morphological profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Many gene knockouts invoked DEGs relating to matrix metalloproteinases and interferon-induced proteins. We have prioritized genes at four loci of interest to identify gene knockouts that may contribute to the pathogenesis of POAG, including ANGPTL2, LMX1B, CAV1, and KREMEN1. Three genetic networks of gene knockouts with similar transcriptomic profiles were identified, suggesting a synergistic function in trabecular meshwork cell physiology. TEK knockout caused significant upregulation of nuclear granularity on morphological analysis, while knockout of TRIOBP, TMCO1 and PLEKHA7 increased granularity and intensity of actin and the cell-membrane.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>High-throughput analysis of cellular structure and function through multiplex fluorescent single-cell analysis and scRNA-seq assays enabled the direct study of genetic perturbations at the single-cell resolution. This work provides a framework for investigating the role of genes in the pathogenesis of glaucoma and heterogenous diseases with a strong genetic basis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/hmg\/ddae003","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T08:19:22Z","timestamp":1704874762000},"page":"739-751","source":"Crossref","is-referenced-by-count":16,"title":["High throughput functional profiling of genes at intraocular pressure loci reveals distinct networks for glaucoma"],"prefix":"10.1093","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7118-2582","authenticated-orcid":false,"given":"Connor J","family":"Greatbatch","sequence":"first","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania , 17 Liverpool Street, Hobart, Tasmania 7000 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyi","family":"Lu","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania , 17 Liverpool Street, Hobart, Tasmania 7000 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandy","family":"Hung","sequence":"additional","affiliation":[{"name":"Centre for Eye Research Australia, University of Melbourne , Royal Victorian Eye and Ear Hospital, 32 Gisborne St, East Melbourne 3002 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J","family":"Barnett","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania , 17 Liverpool Street, Hobart, Tasmania 7000 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristof","family":"Wing","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University 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Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen M","family":"Siggs","sequence":"additional","affiliation":[{"name":"Garvan Institute of Medical Research , 384 Victoria St, Darlinghurst, Sydney, NSW 2010 , Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, Short Street, St George Hospital KOGARAH UNSW , Sydney 2217 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A","family":"Mackey","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania , 17 Liverpool Street, Hobart, Tasmania 7000 , Australia"},{"name":"Lions Eye Institute , Centre for Vision Sciences, , 2 Verdun Street Nedlands WA 6009 , Australia"},{"name":"University of Western Australia , Centre for Vision Sciences, , 2 Verdun Street Nedlands WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony L","family":"Cook","sequence":"additional","affiliation":[{"name":"Wicking Dementia Research and Education Centre, University of Tasmania , 17 Liverpool Street, Hobart, TAS 7000 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Senabouth","sequence":"additional","affiliation":[{"name":"Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research , 384 Victoria St, Darlinghurst, Sydney, NSW 2010 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guei-Sheung","family":"Liu","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania , 17 Liverpool Street, Hobart, Tasmania 7000 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie E","family":"Craig","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Flinders University, Flinders Medical Centre , 1 Flinders Dr, Bedford Park, South Australia 5042 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"MacGregor","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute , 300 Herston Rd, Herston, Brisbane 4006 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E","family":"Powell","sequence":"additional","affiliation":[{"name":"Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research , 384 Victoria St, Darlinghurst, Sydney, NSW 2010 , Australia"},{"name":"UNSW Cellular Genomics Futures Institute, University of New South Wales , 384 Victoria St, Darlinghurst, Sydney, NSW 2010 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5123-5999","authenticated-orcid":false,"given":"Alex W","family":"Hewitt","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research, University of Tasmania , 17 Liverpool Street, Hobart, Tasmania 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