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Series GSE223658 Query DataSets for GSE223658
Status Public on Nov 08, 2023
Title Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms [Spec-seq]
Organism synthetic construct
Experiment type Other
Summary 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.
 
Overall design Two Spec-seq libararies containing monomeric HD motif variants on the sense or antisense strand were designed to profile the binding specificity of WT and mutant CRX HDs. The two libraries were mixed in equal molar ratio in the Spec-seq experiments.
 
Contributor(s) Zheng Y
Citation(s) 37963072
Submission date Jan 24, 2023
Last update date Dec 06, 2023
Contact name Yiqiao Zheng
E-mail(s) yiqiao.zheng@wustl.edu
Phone 314-747-4351
Organization name Washington University in St Louis
Department Department of Ophthalmology & Visual Sciences
Lab Shiming Chen, Ph.D.
Street address 517 South Euclid Avenue
City Saint Louis
State/province Missouri
ZIP/Postal code 63110
Country USA
 
Platforms (1)
GPL17769 Illumina MiSeq (synthetic construct)
Samples (16)
GSM6970182 Spec-seq_wt_1f
GSM6970183 Spec-seq_wt_1m
GSM6970184 Spec-seq_wt_2f
This SubSeries is part of SuperSeries:
GSE223659 Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms
Relations
BioProject PRJNA927050

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE223658_e80a_1_RBE.txt.gz 8.9 Kb (ftp)(http) TXT
GSE223658_e80a_2_RBE.txt.gz 8.9 Kb (ftp)(http) TXT
GSE223658_k88n_1_RBE.txt.gz 7.3 Kb (ftp)(http) TXT
GSE223658_k88n_2_RBE.txt.gz 7.2 Kb (ftp)(http) TXT
GSE223658_r90w_1_RBE.txt.gz 8.9 Kb (ftp)(http) TXT
GSE223658_r90w_2_RBE.txt.gz 8.9 Kb (ftp)(http) TXT
GSE223658_wt_1_RBE.txt.gz 8.8 Kb (ftp)(http) TXT
GSE223658_wt_2_RBE.txt.gz 8.9 Kb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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