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Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape

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Abstract
Genetic defects such as copy number variations (CNVs) in non-coding regions containing conserved non-coding elements (CNEs) outside the transcription unit of their target gene, can underlie genetic disease. An example of this is the short stature homeobox (SHOX) gene, regulated by seven CNEs located downstream and upstream of SHOX, with proven enhancer capacity in chicken limbs. CNVs of the downstream CNEs have been reported in many idiopathic short stature (ISS) cases, however, only recently have a few CNVs of the upstream enhancers been identified. Here, we set out to provide insight into: (i) the cis-regulatory role of these upstream CNEs in human cells, (ii) the prevalence of upstream CNVs in ISS, and (iii) the chromatin architecture of the SHOX cis-regulatory landscape in chicken and human cells. Firstly, luciferase assays in human U2OS cells, and 4C-seq both in chicken limb buds and human U2OS cells, demonstrated cis-regulatory enhancer capacities of the upstream CNEs. Secondly, CNVs of these upstream CNEs were found in three of 501 ISS patients. Finally, our 4C-seq interaction map of the SHOX region reveals a cis-regulatory domain spanning more than 1 Mb and harbouring putative new cis-regulatory elements.
Keywords
TIME QUANTITATIVE PCR, PSEUDOAUTOSOMAL REGION 1, HOMEOBOX GENE SHOX, LANGER MESOMELIC DYSPLASIA, LERI-WEILL DYSCHONDROSTEOSIS, IDIOPATHIC SHORT STATURE, HUMAN GENOME, TURNER-SYNDROME, COPY NUMBER, CHROMOSOME CONFORMATION

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Chicago
Verdin, Hannah, Ana Fernández-Miñán, Sara Benito-Sanz, Sandra Janssens, Bert Callewaert, Kathleen De Waele, Jean De Schepper, et al. 2015. “Profiling of Conserved Non-coding Elements Upstream of SHOX and Functional Characterisation of the SHOX Cis-regulatory Landscape.” Scientific Reports 5.
APA
Verdin, H., Fernández-Miñán, A., Benito-Sanz, S., Janssens, S., Callewaert, B., De Waele, K., De Schepper, J., et al. (2015). Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape. SCIENTIFIC REPORTS, 5.
Vancouver
1.
Verdin H, Fernández-Miñán A, Benito-Sanz S, Janssens S, Callewaert B, De Waele K, et al. Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape. SCIENTIFIC REPORTS. 2015;5.
MLA
Verdin, Hannah, Ana Fernández-Miñán, Sara Benito-Sanz, et al. “Profiling of Conserved Non-coding Elements Upstream of SHOX and Functional Characterisation of the SHOX Cis-regulatory Landscape.” SCIENTIFIC REPORTS 5 (2015): n. pag. Print.
@article{7083764,
  abstract     = {Genetic defects such as copy number variations (CNVs) in non-coding regions containing conserved non-coding elements (CNEs) outside the transcription unit of their target gene, can underlie genetic disease. An example of this is the short stature homeobox (SHOX) gene, regulated by seven CNEs located downstream and upstream of SHOX, with proven enhancer capacity in chicken limbs. CNVs of the downstream CNEs have been reported in many idiopathic short stature (ISS) cases, however, only recently have a few CNVs of the upstream enhancers been identified. Here, we set out to provide insight into: (i) the cis-regulatory role of these upstream CNEs in human cells, (ii) the prevalence of upstream CNVs in ISS, and (iii) the chromatin architecture of the SHOX cis-regulatory landscape in chicken and human cells. Firstly, luciferase assays in human U2OS cells, and 4C-seq both in chicken limb buds and human U2OS cells, demonstrated cis-regulatory enhancer capacities of the upstream CNEs. Secondly, CNVs of these upstream CNEs were found in three of 501 ISS patients. Finally, our 4C-seq interaction map of the SHOX region reveals a cis-regulatory domain spanning more than 1 Mb and harbouring putative new cis-regulatory elements.},
  articleno    = {17667},
  author       = {Verdin, Hannah and Fern{\'a}ndez-Mi{\~n}{\'a}n, Ana and Benito-Sanz, Sara and Janssens, Sandra and Callewaert, Bert and De Waele, Kathleen and De Schepper, Jean and Fran\c{c}ois, Inge and Menten, Bj{\"o}rn and Heath, Karen E and G{\'o}mez-Skarmeta, Jos{\'e} Luis and De Baere, Elfride},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keyword      = {TIME QUANTITATIVE PCR,PSEUDOAUTOSOMAL REGION 1,HOMEOBOX GENE SHOX,LANGER MESOMELIC DYSPLASIA,LERI-WEILL DYSCHONDROSTEOSIS,IDIOPATHIC SHORT STATURE,HUMAN GENOME,TURNER-SYNDROME,COPY NUMBER,CHROMOSOME CONFORMATION},
  language     = {eng},
  pages        = {9},
  title        = {Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape},
  url          = {http://dx.doi.org/10.1038/srep17667},
  volume       = {5},
  year         = {2015},
}

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