Transcription factor interactions explain the context-dependent activity of CRX binding sites
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ABSTRACT:
PROVIDER: PRJNA937735 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23592437.fastq.gz | Fastqsanger.gz | |||
| SRR23592438.fastq.gz | Fastqsanger.gz | |||
| SRR23592439.fastq.gz | Fastqsanger.gz | |||
| SRR23592440.fastq.gz | Fastqsanger.gz | |||
| SRR23592441.fastq.gz | Fastqsanger.gz |
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Project description:We assessed how the effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory sequence (CRS) depend on the local sequence context. We constructed a library of synthetic CRSs composed of TFBSs enriched in mouse photoreceptors and assayed them by massively parallel reporter assay in live mouse retina. We used the resulting data to train neural network-based models that predict CRS activity from sequence.
2023-03-05 | GSE225867 | GEO
Project description:CRX is a key transcript factor for photoreceptor development and homeostasis. We have characterized the CRX-dependent cis-regulatory network by ChIP-chip analysis of 2 month old BL/6 mouse retinas using Affymetrix Mouse Promoter 1.0 arrays
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Project description:To analyze the expression profile in the Otx2 knock-in (a knock-in mouse line expressing Otx2 from the Crx locus on chromosome 7) and Crx knockout retina, we performed a microarray analysis using wild-type (Crx +/+), Otx2 KI (Crx Otx2/Otx2) and Crx KO (Crx -/-) retina at P12.
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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
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 | GSE223657 | GEO
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
Project description:Leber congenital amaurosis (LCA) includes congenital or early-onset blinding diseases, characterized by vision loss together with nystagmus and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA. While most LCA is recessive, mutations in the homeodomain transcription factor gene CRX lead to autosomal dominant LCA. The mechanism of CRX-LCA is not understood. Here, we report a new spontaneous mouse mutant carrying a frameshift mutation in Crx (CrxRip). We show that, unlike Crx-/- mouse retina, the dominant Crx c.763del1 mutation in CrxRip results in congenital blindness with complete loss of ERG, yet the photoreceptors do not degenerate. Dominant CRX frameshift mutations associated with LCA mimic the CrxRip phenotype that can be rescued by Crx. RNA-Seq profiling reveals progressive and complete loss of rod differentiation factor Nrl in CrxRip, while residual Nrl remains in Crx-/- retina. Moreover, Nrl partially restores the rod phenotype in CrxRip/+ mice. We show that the binding of Otx2 to Nrl promoter is obliterated in CrxRip mutant, and ectopic Otx2 can rescue the rod phenotype. Therefore, Otx2 is required to maintain Nrl expression in developing rods to consolidate rod fate. Our studies provide the mechanism of congenital blindness caused by dominant CRX mutations and should assist in therapeutic design. Retinal samples were harvested from WT, CrxRip/+, CrxRip/Rip, Crx-/- and Nrl-/- retina at postnatal days 2 and 21 for whole transcriptome sequencing (RNAseq). Each sample included 2 independent frozen retina and experiments were performed in duplicates. RNA-seq transcriptome libraries were constructed from 1 ?g of total RNA.
2014-01-13 | E-GEOD-52006 | biostudies-arrayexpress
Project description:P10 retinal gene expression analysis of the homozygous Crx Knock-OUT or Knock-IN mice carrying the mutation E168d2 or R90W. Results provide important information about the retinal genes affected by mutations in the transcription factor Crx, which have been implicated in human retinopathies. PolyA RNA isolated from 3 Sex-matched (1M,1F) pairs of P10 mouse retinas from each genotype (WT, E168d2neo/d2neo, R90Wneo/Wneo, and Crx -/-)
2013-12-01 | E-GEOD-51184 | biostudies-arrayexpress
Project description:Leber congenital amaurosis (LCA) includes congenital or early-onset blinding diseases, characterized by vision loss together with nystagmus and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA. While most LCA is recessive, mutations in the homeodomain transcription factor gene CRX lead to autosomal dominant LCA. The mechanism of CRX-LCA is not understood. Here, we report a new spontaneous mouse mutant carrying a frameshift mutation in Crx (CrxRip). We show that, unlike Crx-/- mouse retina, the dominant Crx c.763del1 mutation in CrxRip results in congenital blindness with complete loss of ERG, yet the photoreceptors do not degenerate. Dominant CRX frameshift mutations associated with LCA mimic the CrxRip phenotype that can be rescued by Crx. RNA-Seq profiling reveals progressive and complete loss of rod differentiation factor Nrl in CrxRip, while residual Nrl remains in Crx-/- retina. Moreover, Nrl partially restores the rod phenotype in CrxRip/+ mice. We show that the binding of Otx2 to Nrl promoter is obliterated in CrxRip mutant, and ectopic Otx2 can rescue the rod phenotype. Therefore, Otx2 is required to maintain Nrl expression in developing rods to consolidate rod fate. Our studies provide the mechanism of congenital blindness caused by dominant CRX mutations and should assist in therapeutic design.
2014-01-13 | GSE52006 | GEO
Project description:The cone-rod homeobox gene (Crx) encodes Crx, a transcription factor selectively expressed in two cell types, retinal photoreceptors and the melatonin secreting pinealocytes of the pineal gland. In this report the role of Crx in regulating gene expression in the mammalian pineal gland was extended using Affymetrix GeneChip technology. Deletion of Crx results in broad modulation of the mouse pineal transcriptome, including a >2-fold downregulation of 543 genes and a >2-fold upregulation of 745 genes. In addition to Crx, there was a >10-fold downregulation of 13 other genes. Of special interest was the discovery of a link between Crx and the homeobox gene Hoxc4, which was upregulated ~20-fold in the Crx-/- pineal gland. Analysis of night and day expression of genes indicated that a set of 51 genes exhibited differential expression in control animals. Of these genes, only eight were also differentially expressed in Crx-/- animals. This group included Aanat, which encodes the enzyme that controls the daily rhythm in melatonin synthesis in the vertebrate pineal gland. Accordingly, Crx appears to be essential for the 24-hour rhythmic component of expression of some genes in the pineal gland. In the Crx-/- mouse pineal gland, 41 genes exhibited differential night/day expression that was not seen in control animals, suggesting that Crx may function to modulate rhythmic expression of these genes as well. Together, the results of this investigation indicate that Crx broadly modulates the pineal transcriptome, perhaps in part through suppressive effects on expression of the homeobox gene Hoxc4. Pineal glands from control (129sv) mice and Crx-/- mice were collected at ZT6 and ZT20 for RNA extraction and hybridization on Affymetrix mouse 430_2 chip. Each condition were performed as triplicats. SUPPLEMENTARY FILES: The GCOS signal intensity data were analyzed using ChipInspector (Genomatix) version 2.1. FDR= 0, p-value <0.05, cut off=1, region size = 300 bp and 4 and 5 significant probes. Log(2) fold change independently of time of day. Up regulated genes: genes which are up regulated in Crx-/- compared to the control; down regulated genes: genes which are down regulated in Crx-/- compared to the control.
2012-01-01 | E-GEOD-24625 | biostudies-arrayexpress