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The chromosome 17q super-enhancer landscape in neuroblastoma

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Abstract
Introduction: Neuroblastoma (NB) is an agressive deadly pediatric cancer of the developing sympatho-adrenergic nervous system. NBs are characterised by a very low mutation burden while exhibiting highly recurrent DNA copy number alterations, including chromosome 17q gain in most of the aggressive NBs. Recently, we also reported frequent gain of a chromosome 11 mouse segment syntenic to human chromosome 17q in a MYCN driven NB mouse model, supporting a crucial role for 17q gain in human NB formation. So far, identification of the culprit driver genes on 17q was hampered by the large size of the commonly gained segment. Here, we used an integrated genomic approach to prioritize candidate 17q driver genes based on the presence of (super-)enhancers for genes upregulated during tumor formation in the MYCN transgenic mice. Material and Methods: Chromatin immunoprecipitation sequencing (ChIP-seq) for the H3K27ac chromatin mark was performed on 8 NB cell lines with different genomic profiles to explore the NB (super-) enhancer landscape. We included 7 cell lines with 17q gain and one cell line with normal chromosome 17 status. Four cell lines were MYCN amplified. Fastq data were aligned to the reference genome hg19 using bowtie2, subsequently peak calling was performed with MACS2 and finally the Rose algorithm was used to cluster the enhancers to 12.5 Kb and rank them according to H3K27ac signal in order to define super-enhancers. Results and Discussion: A significant higher number of active super-enhancers on 17q was observed in MYCN amplified NB cell lines, suggesting that MYCN acts as an amplifier to boost the activation of super-enhancers on 17q and leading to overexpression of genes marked by these super-enhancers. Further analysis of the ChIP-seq data also showed that the number of active super-enhancers on 17q was independent of 17q status. Next, we have prioritized superenhancer marked 17q genes for further functional analysis using a previously established gene expression data set comparing hyperplastic lesions of normal and MYCN transgenic mice at different time points after birth as well as full blown MYCN driven mouse tumors. This allowed us to mark a top list of superenhancer marked 17q genes for further functional testing.
Keywords
neuroblastoma, 17q, super-enhancer

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MLA
Decaesteker, Bieke, Anton Henssen, Wouter Van Loocke, et al. “The Chromosome 17q Super-enhancer Landscape in Neuroblastoma.” European Cancer Epigenetics Conference, 1st, Abstracts. 2015. 39–39. Print.
APA
Decaesteker, B., Henssen, A., Van Loocke, W., Beckers, A., Aerts, S., Schulte, J., De Preter, K., et al. (2015). The chromosome 17q super-enhancer landscape in neuroblastoma. European Cancer Epigenetics conference, 1st, Abstracts (pp. 39–39). Presented at the 1st European Cancer Epigenetics conference.
Chicago author-date
Decaesteker, Bieke, Anton Henssen, Wouter Van Loocke, Anneleen Beckers, Stein Aerts, Johannes Schulte, Katleen De Preter, and Franki Speleman. 2015. “The Chromosome 17q Super-enhancer Landscape in Neuroblastoma.” In European Cancer Epigenetics Conference, 1st, Abstracts, 39–39.
Chicago author-date (all authors)
Decaesteker, Bieke, Anton Henssen, Wouter Van Loocke, Anneleen Beckers, Stein Aerts, Johannes Schulte, Katleen De Preter, and Franki Speleman. 2015. “The Chromosome 17q Super-enhancer Landscape in Neuroblastoma.” In European Cancer Epigenetics Conference, 1st, Abstracts, 39–39.
Vancouver
1.
Decaesteker B, Henssen A, Van Loocke W, Beckers A, Aerts S, Schulte J, et al. The chromosome 17q super-enhancer landscape in neuroblastoma. European Cancer Epigenetics conference, 1st, Abstracts. 2015. p. 39–39.
IEEE
[1]
B. Decaesteker et al., “The chromosome 17q super-enhancer landscape in neuroblastoma,” in European Cancer Epigenetics conference, 1st, Abstracts, Maastricht, The Netherlands, 2015, pp. 39–39.
@inproceedings{6961193,
  abstract     = {Introduction: Neuroblastoma (NB) is an agressive deadly pediatric cancer of the developing sympatho-adrenergic nervous system. NBs are characterised by a very low mutation burden while exhibiting highly recurrent DNA copy number alterations, including chromosome 17q gain in most of the aggressive NBs. Recently, we also reported frequent gain of a chromosome 11 mouse segment syntenic to human chromosome 17q in a MYCN driven NB mouse model, supporting a crucial role for 17q gain in human NB formation. So far, identification of the culprit driver genes on 17q was hampered by the large size of the commonly gained segment. Here, we used an integrated genomic approach to prioritize candidate 17q driver genes based on the presence of (super-)enhancers for genes upregulated during tumor formation in the MYCN transgenic mice. 
Material and Methods: Chromatin immunoprecipitation sequencing (ChIP-seq) for the H3K27ac chromatin mark was performed on 8 NB cell lines with different genomic profiles to explore the NB (super-) enhancer landscape. We included 7 cell lines with 17q gain and one cell line with normal chromosome 17 status. Four cell lines were MYCN amplified. Fastq data were aligned to the reference genome hg19 using bowtie2, subsequently peak calling was performed with MACS2 and finally the Rose algorithm was used to cluster the enhancers to 12.5 Kb and rank them according to H3K27ac signal in order to define super-enhancers. 
Results and Discussion: A significant higher number of active super-enhancers on 17q was observed in MYCN amplified NB cell lines, suggesting that MYCN acts as an amplifier to boost the activation of super-enhancers on 17q and leading to overexpression of genes marked by these super-enhancers. Further analysis of the ChIP-seq data also showed that the number of active super-enhancers on 17q was independent of 17q status. Next, we have prioritized superenhancer marked 17q genes for further functional analysis using a previously established gene expression data set comparing hyperplastic lesions of normal and MYCN transgenic mice at different time points after birth as well as full blown MYCN driven mouse tumors. This allowed us to mark a top list of superenhancer marked 17q genes for further functional testing.},
  author       = {Decaesteker, Bieke and Henssen, Anton and Van Loocke, Wouter and Beckers, Anneleen and Aerts, Stein and Schulte, Johannes and De Preter, Katleen and Speleman, Franki},
  booktitle    = {European Cancer Epigenetics conference, 1st, Abstracts},
  keywords     = {neuroblastoma,17q,super-enhancer},
  language     = {eng},
  location     = {Maastricht, The Netherlands},
  pages        = {39--39},
  title        = {The chromosome 17q super-enhancer landscape in neuroblastoma},
  year         = {2015},
}