Structural variants create new topological-associated domains and ectopic retinal nhancer-gene contact in dominant retinitis pigmentosa

dc.contributor.authorde Bruijn, S.E.
dc.contributor.authorFiorentino, A
dc.contributor.authorOttaviani, D.
dc.contributor.authorFanucchi, S.
dc.contributor.authorMelo, U.S.
dc.contributor.authorCorral-Serrano, J.C.
dc.contributor.authorMulders, T.
dc.contributor.authorGeorgiou, M.
dc.contributor.authorRivolta, C.
dc.contributor.authorPontikos, N.
dc.contributor.authorArno, G.
dc.contributor.authorRoberts, L.
dc.contributor.authorGreenberg, J.
dc.contributor.authorAlbert, S.
dc.contributor.authorGilissen, C.
dc.contributor.authorAben, M.
dc.contributor.authorRebello, G.
dc.contributor.authorMead, S.
dc.contributor.authorRaymond, F.L.
dc.contributor.authorCorominas, J.
dc.contributor.authorSmith, C.E.L.
dc.contributor.authorKremer, H.
dc.contributor.authorDownes, S.
dc.contributor.authorBlack, G.C.
dc.contributor.authorWebster, A.R.
dc.contributor.authorInglehearn, C.F.
dc.contributor.authorvan den Born, L.I.
dc.contributor.authorKoenekoop, R.K.
dc.contributor.authorMichaelides, M.
dc.contributor.authorRamesar, R.S.
dc.contributor.authorHoyng, C.B.
dc.contributor.authorMundlos, S.
dc.contributor.authorMhlanga, M.M.
dc.contributor.authorCremers, F.P.M.
dc.contributor.authorCheetham, M.E.
dc.contributor.authorRoosing, S.
dc.contributor.authorHardcastle, A.J.
dc.contributor.departmentJacquie Greenberg, Lisa Roberts: University of Cape Town/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, 7935, South Africaen_US
dc.description.abstractThe cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.en_US
dc.identifier.citationde Bruijn SE, Fiorentino A, Ottaviani D, Fanucchi S, Melo US, Corral-Serrano JC, Mulders T, Georgiou M, Rivolta C, Pontikos N, Arno G, Roberts L, Greenberg J, Albert S, Gilissen C, Aben M, Rebello G, Mead S, Raymond FL, Corominas J, Smith CEL, Kremer H, Downes S, Black GC, Webster AR, Inglehearn CF, van den Born LI, Koenekoop RK, Michaelides M, Ramesar RS, Hoyng CB, Mundlos S, Mhlanga MM, Cremers FPM, Cheetham ME, Roosing S, Hardcastle AJ. Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa. Am J Hum Genet. 2020 Nov 5;107(5):802-814. doi: 10.1016/j.ajhg.2020.09.002. Epub 2020 Oct 5.en_US
dc.identifier.journalAmerican Journal of Human Geneticsen_US
dc.publisherCell Pressen_US
dc.research.unitPrecision and Genomic Medicine (New)en_US
dc.rightsAttribution 3.0 United States*
dc.subjectDominant retinitis pigmentosaen_US
dc.subjectEctopic expressionen_US
dc.subjectPhotoreceptor precursors cellsen_US
dc.subjectRetinal organoidsen_US
dc.subjectStem cellsen_US
dc.subjectStructural variantsen_US
dc.subjectWhole-genome sequencingen_US
dc.subjectTopologically associated domainsen_US
dc.titleStructural variants create new topological-associated domains and ectopic retinal nhancer-gene contact in dominant retinitis pigmentosaen_US
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
de Bruijn SE_2020_Structural variants .pdf
2.37 MB
Adobe Portable Document Format
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
1.71 KB
Item-specific license agreed upon to submission