Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa
| Autor(a) principal: | |
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| Data de Publicação: | 2020 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/46284 |
Resumo: | © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
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Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosaWhole-genome sequencingDominant retinitis pigmentosaRP17Structural variantsEctopic expressionStem cellsRetinal organoidsPhotoreceptor precursors cellsHi-CTopologically associated domainsGDPD© 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)The 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.ElsevierRepositório da Universidade de Lisboade Bruijn, Suzanne E.Fiorentino, AlessiaOttaviani, DanieleFanucchi, StephanieMelo, Uirá S.Corral-Serrano, Julio C.Mulders, TimoGeorgiou, MichalisRivolta, CarloPontikos, NikolasArno, GavinRoberts, LisaGreenberg, JacquieAlbert, SilviaGilissen, ChristianAben, MarcoRebello, GeorgeMead, SimonRaymond, F. LucyCorominas, JordiSmith, Claire E. L.Kremer, HannieDownes, SusanBlack, Graeme C.Webster, Andrew R.Inglehearn, Chris F.van den Born, L. IngeborghKoenekoop, Robert K.Michaelides, MichelRamesar, Raj S.Hoyng, Carel B.Mundlos, StefanMhlanga, MusaCremers, Frans P. M.Cheetham, Michael E.Roosing, SusanneHardcastle, Alison J.2021-02-11T13:36:31Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/46284engAm J Hum Genet. 2020 Nov 5;107(5):802-8140002-929710.1016/j.ajhg.2020.09.0021537-6605info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-11-20T18:03:22Zoai:repositorio.ul.pt:10451/46284Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-11-20T18:03:22Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa |
| title |
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa |
| spellingShingle |
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa de Bruijn, Suzanne E. Whole-genome sequencing Dominant retinitis pigmentosa RP17 Structural variants Ectopic expression Stem cells Retinal organoids Photoreceptor precursors cells Hi-C Topologically associated domains GDPD |
| title_short |
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa |
| title_full |
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa |
| title_fullStr |
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa |
| title_full_unstemmed |
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa |
| title_sort |
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa |
| author |
de Bruijn, Suzanne E. |
| author_facet |
de Bruijn, Suzanne E. Fiorentino, Alessia Ottaviani, Daniele Fanucchi, Stephanie Melo, Uirá S. Corral-Serrano, Julio C. Mulders, Timo Georgiou, Michalis Rivolta, Carlo Pontikos, Nikolas Arno, Gavin Roberts, Lisa Greenberg, Jacquie Albert, Silvia Gilissen, Christian Aben, Marco Rebello, George Mead, Simon Raymond, F. Lucy Corominas, Jordi Smith, Claire E. L. Kremer, Hannie Downes, Susan Black, Graeme C. Webster, Andrew R. Inglehearn, Chris F. van den Born, L. Ingeborgh Koenekoop, Robert K. Michaelides, Michel Ramesar, Raj S. Hoyng, Carel B. Mundlos, Stefan Mhlanga, Musa Cremers, Frans P. M. Cheetham, Michael E. Roosing, Susanne Hardcastle, Alison J. |
| author_role |
author |
| author2 |
Fiorentino, Alessia Ottaviani, Daniele Fanucchi, Stephanie Melo, Uirá S. Corral-Serrano, Julio C. Mulders, Timo Georgiou, Michalis Rivolta, Carlo Pontikos, Nikolas Arno, Gavin Roberts, Lisa Greenberg, Jacquie Albert, Silvia Gilissen, Christian Aben, Marco Rebello, George Mead, Simon Raymond, F. Lucy Corominas, Jordi Smith, Claire E. L. Kremer, Hannie Downes, Susan Black, Graeme C. Webster, Andrew R. Inglehearn, Chris F. van den Born, L. Ingeborgh Koenekoop, Robert K. Michaelides, Michel Ramesar, Raj S. Hoyng, Carel B. Mundlos, Stefan Mhlanga, Musa Cremers, Frans P. M. Cheetham, Michael E. Roosing, Susanne Hardcastle, Alison J. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
de Bruijn, Suzanne E. Fiorentino, Alessia Ottaviani, Daniele Fanucchi, Stephanie Melo, Uirá S. Corral-Serrano, Julio C. Mulders, Timo Georgiou, Michalis Rivolta, Carlo Pontikos, Nikolas Arno, Gavin Roberts, Lisa Greenberg, Jacquie Albert, Silvia Gilissen, Christian Aben, Marco Rebello, George Mead, Simon Raymond, F. Lucy Corominas, Jordi Smith, Claire E. L. Kremer, Hannie Downes, Susan Black, Graeme C. Webster, Andrew R. Inglehearn, Chris F. van den Born, L. Ingeborgh Koenekoop, Robert K. Michaelides, Michel Ramesar, Raj S. Hoyng, Carel B. Mundlos, Stefan Mhlanga, Musa Cremers, Frans P. M. Cheetham, Michael E. Roosing, Susanne Hardcastle, Alison J. |
| dc.subject.por.fl_str_mv |
Whole-genome sequencing Dominant retinitis pigmentosa RP17 Structural variants Ectopic expression Stem cells Retinal organoids Photoreceptor precursors cells Hi-C Topologically associated domains GDPD |
| topic |
Whole-genome sequencing Dominant retinitis pigmentosa RP17 Structural variants Ectopic expression Stem cells Retinal organoids Photoreceptor precursors cells Hi-C Topologically associated domains GDPD |
| description |
© 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z 2021-02-11T13:36:31Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/46284 |
| url |
http://hdl.handle.net/10451/46284 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
Am J Hum Genet. 2020 Nov 5;107(5):802-814 0002-9297 10.1016/j.ajhg.2020.09.002 1537-6605 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Elsevier |
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Elsevier |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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mluisa.alvim@gmail.com |
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1817549122875424768 |