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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): synthetic construct Mus musculus

PROVIDER: GSE223659 | GEO | 2023/11/08

REPOSITORIES: GEO

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Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [RNA-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 | GSE223439 | GEO

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

2023-11-08 | GSE223658 | GEO

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

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 [Spec-seq]

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

| PRJNA927050 | 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 [RNA-seq]

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

| PRJNA926323 | ENA

Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominant <i>CRX</i> retinopathy models.

Project description:Paired-class homeodomain transcription factors (HD TFs) play essential roles in vertebrate development, and their mutations are linked to human diseases. One unique feature of paired-class HD is cooperative dimerization on specific palindrome DNA sequences. Yet, the functional significance of HD cooperative dimerization in animal development and its dysregulation in diseases remain elusive. Using the retinal TF Cone-rod Homeobox (CRX) as a model, we have studied how blindness-causing mutations in the paired HD, p.E80A and p.K88N, alter CRX's cooperative dimerization, lead to gene misexpression and photoreceptor developmental deficits in dominant manners. CRXE80A maintains binding at monomeric WT CRX motifs but is deficient in cooperative binding at dimeric motifs. CRXE80A's cooperativity defect impacts the exponential increase of photoreceptor gene expression in terminal differentiation and produces immature, non-functional photoreceptors in the CrxE80A retinas. CRXK88N is highly cooperative and localizes to ectopic genomic sites with strong enrichment of dimeric HD motifs. CRXK88N's altered biochemical properties disrupt CRX's ability to direct dynamic chromatin remodeling during development to activate photoreceptor differentiation programs and silence progenitor programs. Our study here provides in vitro and in vivo molecular evidence that paired-class HD cooperative dimerization regulates neuronal development and dysregulation of cooperative binding contributes to severe dominant blinding retinopathies.

| S-EPMC10979960 | biostudies-literature

Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominant CRX retinopathy models

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

2024-11-22 | GSE256215 | GEO

Aberrant homeodomain-DNA cooperative dimerization underlies distinct developmental defects in two dominant CRX retinopathy models [MPRA]

Project description:Paired-class homeodomain transcription factors (HD TFs) play essential roles in vertebrate development, and their mutations are linked to human diseases. One unique feature of paired-class HD is cooperative dimerization on specific palindrome DNA sequences. Yet, the functional significance of HD cooperative dimerization in animal development and its dysregulation in diseases remain elusive. Using the retinal TF Cone-rod Homeobox (CRX) as a model, we have studied how blindness-causing mutations in the paired HD, p.E80A and p.K88N, alter CRX’s cooperative dimerization, lead to gene misexpression and photoreceptor developmental deficits in dominant manners. CRXE80A maintains binding at monomeric WT CRX motifs but is deficient in cooperative binding at dimeric motifs. CRXE80A’s dimerization defect impacts the exponential increase of photoreceptor gene expression in terminal differentiation and produces immature, non-functional photoreceptors in the CrxE80A retinas. CRXK88N is highly cooperative and localizes to ectopic genomic sites with strong enrichment of dimeric HD motifs. CRXK88N’s altered biochemical properties disrupt CRX’s ability to direct dynamic chromatin remodeling during development to activate photoreceptor differentiation programs and silence progenitor programs. Our study here provides in vitro and in vivo molecular evidence that paired-class HD cooperative dimerization regulates neuronal development and dysregulation of cooperative binding contributes to severe dominant blinding retinopathies.

2024-11-22 | GSE256214 | GEO

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