Mapping the
            <i>cis</i>
            -regulatory architecture of the human retina reveals noncoding genetic variation in disease

Cherry, Timothy J.; Yang, Marty G.; Harmin, David A.; Tao, Peter; Timms, Andrew E.; Bauwens, Miriam; Allikmets, Rando; Jones, E. M.; Chen, Rui; Baere, Elfride De; Greenberg, Michael E.

doi:10.1073/pnas.1922501117

Cited by 82 publications

(124 citation statements)

References 73 publications

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“…Analysis of H3K27Ac ChIP-seq data in the same region revealed several active enhancers located within the YPEL2 TAD, which are enriched for retinal transcription factor binding sites, including NRL, CRX, and OTX2. 25 These enhancers were located 5′ of the CTCF boundary site within LINC01476. (C) Schematic representation of the YPEL2 TAD structure.…”

Section: Resultsmentioning

confidence: 99%

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa

Bruijn

Fiorentino²,

Ottaviani³

et al. 2020

The American Journal of Human Genetics

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Summary 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.

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Section: Resultsmentioning

confidence: 99%

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa

Bruijn

Fiorentino²,

Ottaviani³

et al. 2020

The American Journal of Human Genetics

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“…Indeed, CNE1 has sequence similarity with a repressive element upstream of Xenopus homolog Ath5, which prevents precocious retinal expression (70). In addition, one open chromatin peak in the mouse ATAC-seq profile, 0.7 kb upstream from Di, is not conserved at the DNA sequence level (100) and is not found in human embryonic retinal open chromatin (98). If this element augments activity of the mouse Atoh7 PE, it may help explain the species difference in SE deletion phenotypes.…”

Section: Discussionmentioning

confidence: 99%

TheAtoh7remote enhancer provides transcriptional robustness during retinal ganglion cell development

Miesfeld

Ghiasvand

Marsh-Armstrong

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The retinal ganglion cell (RGC) competence factor ATOH7 is dynamically expressed during retinal histogenesis. ATOH7 transcription is controlled by a promoter-adjacent primary enhancer and a remote shadow enhancer (SE). Deletion of the ATOH7 human SE causes nonsyndromic congenital retinal nonattachment (NCRNA) disease, characterized by optic nerve aplasia and total blindness. We used genome editing to model NCRNA in mice. Deletion of the murine SE reduces Atoh7 messenger RNA (mRNA) fivefold but does not recapitulate optic nerve loss; however, SEdel/knockout (KO) trans heterozygotes have thin optic nerves. By analyzing Atoh7 mRNA and protein levels, RGC development and survival, and chromatin landscape effects, we show that the SE ensures robust Atoh7 transcriptional output. Combining SE deletion and KO and wild-type alleles in a genotypic series, we determined the amount of Atoh7 needed to produce a normal complement of adult RGCs, and the secondary consequences of graded reductions in Atoh7 dosage. Together, these data reveal the workings of an evolutionary fail-safe, a duplicate enhancer mechanism that is hard-wired in the machinery of vertebrate retinal ganglion cell genesis.

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“…In addition, many individuals with retinal disease do not have a known disease gene allele. As multiple genes characterized in our study have been associated with retinal diseases, their associated CRMs, or the motifs identified here, can form the basis of a study for causal variants that might affect the expression of a nearby disease gene 86 .…”

Section: Discussionmentioning

confidence: 96%

Otx2 and Oc1 directly regulate the transcriptional program of cone photoreceptor development

Lonfat

Wang

Lee

et al. 2020

Preprint

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AbstractThe vertebrate retina is a highly organized structure of approximately 110 cell types. Retinal progenitor cells (RPCs) produce these cell types in a temporal order that is highly conserved. While some RPCs produce many cell types, some terminally dividing RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). Here, we compared the transcriptomes and chromatin profiles of such a restricted cone/HC RPC with those of other RPCs. We identified many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. We then showed that Otx2 and Oc1 directly regulate the activity of multiple CRMs genome-wide, including near genes important for cone development, such as Rxrg and Neurod1. In addition, we found that Otx2 regulates itself. These results suggest that Otx2 and Oc1 have a broader role than previously appreciated, and deepen our understanding of retinal development, which may benefit therapies for retinal diseases.

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Mapping the cis -regulatory architecture of the human retina reveals noncoding genetic variation in disease

Cited by 82 publications

References 73 publications

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa

TheAtoh7remote enhancer provides transcriptional robustness during retinal ganglion cell development

Otx2 and Oc1 directly regulate the transcriptional program of cone photoreceptor development

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