Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy

被引:15
作者
van de Sompele, Stijn [1 ,2 ]
Small, Kent W. [3 ,4 ]
Cicekdal, Munevver Burcu [1 ,2 ,5 ]
Soriano, Victor Lopez [1 ,2 ]
D'haene, Eva [1 ,2 ]
Shaya, Fadi S. [3 ,4 ]
Agemy, Steven [6 ]
van der Snickt, Thijs [1 ,2 ]
Rey, Alfredo Duenas [1 ,2 ]
Rosseel, Toon [1 ,2 ]
Van Heetvelde, Mattias [1 ,2 ]
Vergult, Sarah [1 ,2 ]
Balikova, Irina [7 ]
Bergen, Arthur A. [8 ,9 ]
Boon, Camiel J. F. [10 ,11 ]
De Zaeytijd, Julie [12 ]
Inglehearn, Chris F. [13 ]
Kousal, Bohdan [14 ,15 ]
Leroy, Bart P. [2 ,12 ,16 ,17 ,18 ]
Rivolta, Carlo [19 ,20 ,21 ]
Vaclavik, Veronika [22 ]
van den Ende, Jenneke [23 ]
van Schooneveld, Mary J. [10 ,24 ]
Gomez-Skarmeta, Jose Luis [25 ,26 ]
Tena, Juan J. [25 ,26 ]
Martinez-Morales, Juan R. [25 ,26 ]
Liskova, Petra [14 ,15 ,27 ]
Vleminckx, Kris [2 ,5 ]
De Baere, Elfride [1 ,2 ]
机构
[1] Univ Ghent, Dept Biomol Med, Ghent, Belgium
[2] Ghent Univ Hosp, Ctr Med Genet, Ghent, Belgium
[3] Macula & Retina Inst, Los Angeles, CA USA
[4] Macula & Retina Inst, Glendale, CA USA
[5] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium
[6] SUNY Downstate Med Ctr Univ, Dept Ophthalmol, Brooklyn, NY USA
[7] Univ Hosp Leuven, Dept Ophthalmol, Leuven, Belgium
[8] Acad Med Ctr, Dept Human Genet, Amsterdam UMC, NL-1105 AZ Amsterdam, Netherlands
[9] Univ Amsterdam, Amsterdam Univ Med Ctr, Queen Emma Ctr Precis Med, Amsterdam, Netherlands
[10] Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Ophthalmol, Amsterdam, Netherlands
[11] Leiden Univ, Dept Ophthalmol, Med Ctr, Leiden, Netherlands
[12] Ghent Univ Hosp, Dept Ophthalmol, Ghent, Belgium
[13] Univ Leeds, Leeds Inst Med Res, Div Mo Lecular Med, Leeds, W Yorkshire, England
[14] Charles Univ Prague, Fac Med 1, Dept Ophthalmol, Prague, Czech Republic
[15] Gen Univ Hosp Prague, Prague, Czech Republic
[16] Univ Ghent, Dept Head & Skin, Ghent, Belgium
[17] Childrens Hosp Philadelphia, Div Ophthalmol, Philadelphia, PA USA
[18] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
[19] Lnstitute Mol & Clin Ophthalmol Basel IOB, Basel, Switzerland
[20] Univ Basel, Dept Ophthalmol, Basel, Switzerland
[21] Univ Leicester, Dept Ge Net & Genome Biol, Leicester, Leics, England
[22] Univ Lausanne, Jules Gonin Eye Hosp, Lausanne, Switzerland
[23] Antwerp Univ Hosp, Ctr Med Genet, Antwerp, Belgium
[24] Diagnost Ctr Complex Visual Disorders, Bartimeus, Zeist, Netherlands
[25] CSIC, Ctr Andaluz Biol Desarrollo, Seville, Spain
[26] Univ Pablo Olavide, Seville, Spain
[27] Charles Univ Prague, Fac Med 1, Dept Paediat & Inherited Metab Disorders, Prague, Czech Republic
基金
欧盟地平线“2020”;
关键词
STRUCTURAL VARIANTS; GENE; FAMILY; PRDM13; GENOME; DUPLICATION; EXPRESSION; DOMAINS; PHOTORECEPTOR; TRANSGENESIS;
D O I
10.1016/j.ajhg.2022.09.013
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCRE5), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMDassociated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.
引用
收藏
页码:2029 / 2048
页数:20
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