Ontology highlight
ABSTRACT:
PROVIDER: PRJEB63626 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| WGS_1165_snp_merged.vcf.csi | Other | |||
| WGS_1165_snp_merged.vcf.gz | Vcf | |||
| WGS_1165_indel_merged.vcf.csi | Other | |||
| WGS_1165_indel_merged.vcf.gz | Vcf |
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Project description:delineating an Ihh enhancer active in mammalian eye development whose variant causes human microphthalmia, anophthalmia and ocular coloboma
2023-07-01 | PRJEB63626 | EVA
Project description:Copy number variations (CNVs) including enhancers frequently appear associated with disease, induced by pathomechanisms that are poorly understood. Here we show through transgenic reporter and genome editing studies in mice that Indian hedgehog (Ihh) is regulated by a constellation of enhancers of unusual complexity and we uncover how duplications within this enhancer architecture cause phenotypes reminiscent of those observed in human patients. At least nine enhancers with distinct combinations of activities orchestrate the expression of Ihh in the digit anlagen, growth plates, skull sutures, and digit tips. Consecutive deletions show that they function in an additive manner resulting in growth defects. Duplications, in contrast, cause not only dose-dependent upregulation of Ihh, but also misexpression, leading to phenotypes influenced by the copy number and relative positioning of individual elements. Taken together, our results uncover a complex regulatory landscape at the Ihh locus and exemplify the intricate and precise control of gene expression during morphogenetic processes.
2017-07-04 | GSE95062 | GEO
Project description:Anophthalmia, microphthalmia and coloboma (AMC) comprise a spectrum of developmental eye disorders, accounting for approximately 20% of childhood visual impairment. While non-coding regulatory sequences are increasingly recognised as contributing to disease burden, characterising their impact on gene function and phenotype remains challenging. Furthermore, little is known of the nature and extent of their contribution to AMC phenotypes. We identified two families with variants in or near MAB21L2. The first proband, with microphthalmia and coloboma, had a likely pathogenic missense variant (c.338G>C; p.[Trp113Ser]), segregating within the family. The second individual, presenting with microphthalmia, had an ~113.5kb homozygous deletion 19.38kb upstream of MAB21L2. Modelling the deletion led to transient small lens and coloboma in zebrafish, and microphthalmia and coloboma in Xenopus tropicalis. Conservation analysis identified 15 non-genic conserved elements (CE) within the deleted region, while ChIP-seq data from mouse embryonic stem cells demonstrated one of these (CE14) binds OTX2, a protein with an established role in eye development. Targeted disruption of CE14 in Xenopus tropicalis recapitulated an ocular coloboma phenotype, supporting its role in eye development. Together, our data provides insights into regulatory mechanisms underlying eye development, and highlights the importance of non-coding sequences as a source of genetic diagnoses in AMC.
2024-08-13 | GSE241711 | GEO
Project description:Mammalian embryo development is dependent on the ability of the uterus to allow and support the implantation of the embryo. Here we demonstrate that ablation of Sox17 specifically in the uterine epithelium results in altered uterine epithelial cell proliferation, uterine gland development and embryo implantation. Uteri lacking Sox17 showed reduction in LIF and IHH signaling which are critical for embryo implantation. ChIP-seq analysis demonstrated that SOX17 binds to a region 19kb 5’ to the Ihh locus. In vivo deletion of this enhancer by the CRISPR-Cas technology reduced Ihh expression in uteri and altered proper endometrial epithelial-stromal interactions required for pregnancy leading to compromised fertility. The SOX17 binding peak at 19kb from the Ihh promoter also bound GATA2, FOXA2 and PGR. Bioinformatic analysis of regions overlapping SOX17, GATA2, FOXA2 and PGR bindings shows 737 genes with these common binding sites. This cluster of transcription factors identified in this enhancer region may represent a combination of regulatory elements essential for uterine epithelial gene expression and differentiation.
2018-08-09 | GSE118327 | GEO
Project description:We test the predicted interferon-inducible enhancer activity of a LINE within the first intron of the IFNAR1 gene (IFNAR1.L1M2a) by knocking out the predicted enhancer using CRISPR, and assessing chromatin and polymerase II occupancy in untreated and interferon beta-treated conditions compared to wildtype cells
2023-03-07 | GSE225824 | GEO
Project description:A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility in children and oncogenic addiction to LMO1 in the tumor cells1. Here we sought to discover the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding sites. SNP rs2168101 G>T was the most highly associated variant (combined P=7.47x10-29, Odds Ratio 0.65, 95% CI: 0.60-0.70) and resided in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumor formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P=0.028) in neuroblastoma primary tumors and ablates GATA3 binding (P=0.007). We demonstrate monoallelic LMO1 expression from the G-containing strand in tumors heterozygous for this SNP as demonstrated both by RNA sequencing (P<0.0001) and reporter assays (P=0.002). These findings show that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumor cells.
2015-10-18 | GSE65664 | GEO
Project description:Mammalian embryo development is dependent on the ability of the uterus to allow and support the implantation of the embryo. Here we demonstrate that ablation of Sox17 specifically in the uterine epithelium results in altered uterine epithelial cell proliferation, uterine gland development and embryo implantation. Uteri lacking Sox17 showed reduction in LIF and IHH signaling which are critical for embryo implantation. ChIP-seq analysis demonstrated that SOX17 binds to a region 19kb 5’ to the Ihh locus. In vivo deletion of this enhancer by the CRISPR-Cas technology reduced Ihh expression in uteri and altered proper endometrial epithelial-stromal interactions required for pregnancy leading to compromised fertility. The SOX17 binding peak at 19kb from the Ihh promoter also bound GATA2, FOXA2 and PGR. Bioinformatic analysis of regions overlapping SOX17, GATA2, FOXA2 and PGR bindings shows 737 genes with these common binding sites. This cluster of transcription factors identified in this enhancer region may represent a combination of regulatory elements essential for uterine epithelial gene expression and differentiation.
2018-08-09 | GSE118264 | GEO
Project description:Cellular models of propionic acidemia were generated using HepG2 cells that were edited by CRISPR gene editing to introduce the pathogenic PCCA c.1285-1416A>G variant associated with propionic acidemia, and a 7 bp deletion of a predicted hnRNP A1 binding motif (c.1285-1411delTAGAACA), which causes complete and partial activation of an 84 bp pseudoexon from intron 14 in the PCCA gene, respectively. Treatment by transfection of splice-switching antisense oligonucleotides (SSO) to block inclusion of the PCCA pseudoexon in mRNA, was used to investigate this as a potential therapeutic strategy.
2023-12-10 | E-MTAB-13549 | biostudies-arrayexpress
Project description:We test the effect of CRISPR knockout of a predicted interferon inducible enhancer within the first intron of the IFNAR1 gene (IFNAR1.L1M2a) on the transcriptional response of GM12878 cells to treatment with interferon beta
2023-03-07 | GSE225825 | GEO
Project description:Previous studies demonstrated that hererozygous missense mutations in IHH could lead to a decreasing IHH signaling efficacy and cause brachydactyly type A1 (BDA1). For revealing difference of Gli1-mediated downstream regulatory effects between wild type IHH signaling and E95K mutant IHH signaling, we have employed whole genome microarray miRNA expression profiling as a discovery platform to identify miRNAs with the potential to take part in Gli1-mediated cis-regulatory network.
2015-10-15 | GSE74020 | GEO