Profiling of upstream enhancers of SHOX in idiopathic short stature and functional characterization of the cis-regulatory landscape of SHOX
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ABSTRACT:
PROVIDER: PRJNA275571 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1805754.fastq.gz | Fastqsanger.gz | |||
| SRR1805755.fastq.gz | Fastqsanger.gz |
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Project description:SHOX mutations and deletions of the downstream regulatory region have been reported in cases with idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Recently, a deletion and duplication of upstream enhancers have been described in ISS. Here, we aimed to evaluate the contribution of upstream copy number variations (CNVs) to the pathogenesis of ISS, to validate the enhancer role of the upstream enhancers in human cells, and to characterize the chromatin architecture of the cis-regulatory landscape of SHOX. CNV analysis of three upstream conserved non-coding elements (CNEs), CNE-5, CNE-3 and CNE-2, in 501 ISS referrals with no established molecular diagnosis revealed two deletions and one duplication. Enhancer activity of the upstream CNEs was corroborated by luciferase assays in human osteosarcoma U2OS cells. In addition, all three CNEs overlap with reported H3K27ac ChIP-seq marks in human embryonic limb buds. To characterize the chromatin interaction profile of the SHOX region, chromosome conformation capture (4C-seq) was performed in chicken embryo limb buds and in U2OS cells, revealing interactions of the upstream CNEs with the SHOX promoter. Moreover, the 4C-seq interaction maps and H3K27ac marks indicated that the cis-regulatory landscape of SHOX encompasses 1 Mb, suggesting additional cis-regulatory elements controlling SHOX.In conclusion, we showed that upstream CNVs of SHOX are rare in ISS and have incomplete penetrance. Chromatin interaction maps, luciferase assays and H3K27ac marks further support an enhancer function for the upstream CNEs. Finally, we demonstrated that the cis-regulatory landscape of SHOX is larger than previously anticipated potentially harboring novel cis-regulatory elements, which may be involved in the pathogenesis of molecularly unsolved ISS cases..
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Project description:Deficiency of the human short stature homeobox-containing gene (SHOX) has been identified in several disorders characterized by reduced height and skeletal anomalies such as Turner, Leri-Weill and Langer syndrome as well as idiopathic short stature. Although highly conserved in vertebrates, rodents lack a SHOX orthologue. Here, we compared gene expression profiles of wildtype and SHOX transgenic mouse limbs using microarray experiments to identify SHOX target genes in the developing limb.
2014-08-13 | GSE47902 | GEO
Project description:Deficiency of the human short stature homeobox-containing gene (SHOX) has been identified in several disorders characterized by reduced height and skeletal anomalies such as Turner, Leri-Weill and Langer syndrome as well as idiopathic short stature. Although highly conserved in vertebrates, rodents lack a SHOX orthologue. Here, we compared gene expression profiles of wildtype and SHOX transgenic mouse limbs using microarray experiments to identify SHOX target genes in the developing limb. Limbs of E12.5 mouse embryos were dissected, fore- and hindlimbs were pooled and genotyped for RNA extraction. RNA from 2 to 4 littermates was pooled per genotype (Wildtype and SHOX transgene) and compared. In total, 2 microarray hybridization experiments were performed using RNA from 2 biological replicate samples for each genotype.
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Project description:Idiopathic short stature is diagnosed by a standing height of less than two standard deviation scores in a specific population adjusted for age and gender and the exclusion of identifiable diseases. A series of studies have confirmed that noncoding RNAs can regulate the chondrocyte proliferation, hypertrophy, and endochondral ossification in the growth plate. In order to analyze and find differentially expressed circRNAs in Idiopathic short stature and healthy controls, we aimed to explore whether differentially expressed circRNAs in idiopathic short stature. Four pairs of blood samples were subjected to microarray analysis using the Arraystar Human CircRNAs Microarray v2 (Arraystar, USA). Compared to normal individuals, in ISS patients, the expression levels of 83 circRNAs were upregulated and those of 62 were downregulated.
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Project description:Idiopathic short stature is diagnosed by a standing height of less than two standard deviation scores in a specific population adjusted for age and gender and the exclusion of identifiable diseases. A series of studies have confirmed that noncoding RNAs can regulate the chondrocyte proliferation, hypertrophy, and endochondral ossification in the growth plate. In order to analyze and find differentially expressed ceRNAs (lncRNAs, circRNAs and mRNAs in peripheral blood exosomes of idiopathic short stature and healthy controls, we aimed to explore whether differentially expressed ceRNAs (lncRNAs, circRNAs and mRNAs) in peripheral blood exosomes of idiopathic short stature. Three pairs of peripheral blood exosomes samples were subjected to microarray analysis using the SBC human ceRNA Microarray.
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Project description:Short stature homeobox-containing gene, MIM 312865 (SHOX) is located within the pseudoautosomal region 1 (PAR1) of the sex chromosomes. Mutations in SHOX or its downstream transcriptional regulatory elements represent the underlying molecular defect in ~60% of Léri-Weill dyschondrosteosis (LWD) and ~5-15% of idiopathic short stature (ISS) patients. Recently, three novel enhancer elements have been identified upstream of SHOX but to date, no PAR1 deletions upstream of SHOX have been observed that only encompass these enhancers in LWD or ISS patients. We set out to search for genetic alterations of the upstream SHOX regulatory elements in 63 LWD and 100 ISS patients with no known alteration in SHOX or the downstream enhancer regions using a specifically designed MLPA assay, which covers the PAR1 upstream of SHOX. An upstream SHOX deletion was identified in an ISS proband and her affected father. The deletion was confirmed and delimited by array-CGH, to extend ~286 kb. The deletion included two of the upstream SHOX enhancers without affecting SHOX. The 13.3-year-old proband had proportionate short stature with normal GH and IGF-I levels. In conclusion, we have identified the first PAR1 deletion encompassing only the upstream SHOX transcription regulatory elements in a family with ISS. The loss of these elements may result in SHOX haploinsufficiency because of decreased SHOX transcription. Therefore, this upstream region should be included in the routine analysis of PAR1 in patients with LWD, LMD and ISS.
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