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Transcriptional activity of an MPRA library containing sequences of genomic origin bound by the transcription factor CRX measured in retinas from mice carrying pathogenic CRX variants

ABSTRACT: Transcriptional activity of an MPRA library containing sequences of genomic origin bound by the transcription factor CRX measured in retinas from mice carrying pathogenic CRX variants

PROVIDER: PRJNA957443 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24219300.fastq.gz	Fastqsanger.gz
	SRR24219301.fastq.gz	Fastqsanger.gz
	SRR24219302.fastq.gz	Fastqsanger.gz
	SRR24219303.fastq.gz	Fastqsanger.gz
	SRR24219304.fastq.gz	Fastqsanger.gz

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Project description:Background: Mutations in the cone-rod-homeobox protein CRX are typically associated with dominant blinding retinopathies with variable age of onset and severity. Five well-characterized mouse models carrying different Crx mutations show a wide range of disease phenotypes. To determine if the phenotype variability correlates with distinct changes in CRX target gene expression, we perform RNA-seq analyses on three of these models and compare the results with published data. Results: Despite dramatic phenotypic differences between the three models tested, graded expression changes in shared sets of genes are detected. Phenotype severity correlates with the down-regulation of genes encoding key rod and cone phototransduction proteins. Interestingly, in increasingly severe mouse models, the transcription of many rod-enriched genes decreases decrementally, whereas that of cone-enriched genes increases incrementally. Unlike down-regulated genes, which show a high degree of CRX binding and dynamic epigenetic profiles in normal retinas, the up-regulated cone-enriched genes do not correlate with direct activity of CRX, but instead likely reflect a change in rod cell-fate integrity. Furthermore, these analyses describe the impact of minor gene expression changes on the phenotype, as two mutants showed marginally distinguishable expression patterns but huge phenotypic differences, including distinct mechanisms of retinal degeneration. Conclusions: Our results implicate a threshold effect of gene expression level on photoreceptor function and survival, highlight the importance of CRX in photoreceptor subtype development and maintenance, and provide a molecular basis for phenotype variability in CRX-associated retinopathies. All genotypes were analyzed in triplicate. Heterozygous and homozygous mutants were all sequenced at P10, the control for which is the P10 C57BL6/J data. Heterozygous mutants were also analyzed at P21, the control for which is the P21 C57BL6/J data.

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Transcriptional activity of an MPRA library containing sequences of genomic origin bound by the transcription factor CRX measured in retinas from mice carrying pathogenic CRX variants

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