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Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [Spec-seq]

ABSTRACT: Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [Spec-seq]

PROVIDER: PRJNA927050 | ENA |

REPOSITORIES: ENA

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Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [Spec-seq]

Project description:Homeodomain transcription factors (HD TFs) are instrumental to vertebrate development. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here we use Cone-Rod Homeobox (CRX) as a model to decipher the disease-causing mechanisms of two HD mutations, p.E80A and p.K88N, that produce severe dominant retinopathies. Through integrated analysis of molecular and functional evidence in vitro and in knock-in mouse models, we uncover two novel gain-of-function mechanisms: p.E80A increases transactivation of canonical CRX target genes in developing photoreceptors; p.K88N alters CRX DNA-binding specificity resulting in binding at ectopic sites and severe perturbation of CRX target gene expression. Both mechanisms produce novel retinal morphological defects and hinders photoreceptor maturation distinct from loss-of-function models. This study reveals the distinct roles of E80 and K88 residues in CRX HD regulatory functions and emphasizes the importance of transcriptional precision in normal development.

2023-11-08 | GSE223658 | GEO

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms

Project description:Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms

| PRJNA927048 | ENA

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [ChIP-seq]

2023-11-08 | GSE223657 | GEO

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [RNA-seq]

2023-11-08 | GSE223439 | GEO

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [RNA-seq]

Project description:Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [RNA-seq]

| PRJNA926323 | ENA

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [ChIP-seq]

Project description:Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [ChIP-seq]

| PRJNA927051 | ENA

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-11-08 | GSE223659 | GEO

Mutations in BCOR, a novel co-repressor of OTX2/CRX, cause pediatric inherited retinal degeneration

Project description:Many transcription factors regulating the production, survival and function of photoreceptor cells in the retina have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here we show that BCL6 co-repressor (BCOR), a polycomb repressive complex I factor mutated in various cancers, negatively regulates photoreceptor gene expression. Using proteomics and promoter assays, we find that BCOR interacts with the photoreceptor transcription factors OTX2 and CRX, and reduces their ability to activate the promoters of photoreceptor-specific genes, such as Rhodopsin and Nrl. CUT&RUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. Finally, we identify missense variants in the human BCOR gene in six families with early-onset X-linked inherited retinal degeneration (IRD). Together, this work uncovers BCOR as a co-repressor of OTX2/CRX essential for photoreceptor cell biology and survival.

2022-09-10 | GSE168129 | GEO

Gene therapy of dominant CRX-Leber congenital amaurosis using patient retinal organoids II

Project description:Mutations in the cone-rod homeobox (CRX) transcription factor lead to distinct retinopathy phenotypes, including early-onset vision impairment in dominant Leber congenital amaurosis (LCA). Using induced pluripotent stem cells (iPSCs) from a patient with CRX-I138fs mutation, we established an in vitro model of CRX-LCA in retinal organoids that exhibit defective photoreceptor maturation by histology and gene profiling including diminished expression of visual opsins. Gene therapy by delivery of an additional correct CRX allele using an AAV vector partially restored photoreceptor phenotype and expression of phototransduction-related genes as revealed by single cell RNA-sequencing. Retinal organoids derived from iPSCs of a second dominant CRX-LCA patient carrying a K88N mutation revealed loss of opsin expression as a common phenotype, which could also be alleviated by AAV-mediated overexpression of CRX. Our studies provide the proof-of-concept for development of gene therapy for dominant CRX-LCA and other CRX-retinopathies.

2021-02-17 | GSE153099 | GEO

Gene therapy of dominant CRX-Leber congenital amaurosis using patient retinal organoids I

2021-02-17 | GSE152939 | GEO