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LncRNAs as novel players in neuroblastoma tumor biology

Dries Rombaut (UGent)
(2019)
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Abstract
In neuroblastoma, several protein coding genes are established as key players in the tumorigenesis and pathogenesis, such as ALK, MYCN and PHOX2B. These proteins regulate a plethora of other genes, however, little is known about their non-coding targets. Based on the combination of RNA sequencing data of 497 primary tumor samples and model systems for MYCN, ALK and PHOX2B, we could demonstrate that each of these key neuroblastoma genes regulate a core set of lincRNAs, some of which were associated with certain disease stages or survival. Furthermore, we analyzed the data to find lincRNAs that modulate the effect or are in charge of the regulation of these genes. Through a state-of-the-art computational workflow, various lincRNAs were identified as a functional member of the networks surrounding these key genes. Both approaches allowed us to establish a core set of lincRNAs with a potential implication in this pediatric malignancy. To confirm one of these results, we have experimentally validated our top candidate, a neuroblastoma specific lincRNA with an association with PHOX2B and overall survival. NESPR (NEuroblastoma Specific Phox2B Regulatory rna) is located in the genomic region of PHOX2B and is a member of the noradrenergic core regulatory circuit (CRC) in charge of neuroblastoma cell identity. Through antisense oligonucleotide (ASO) mediated downregulation of NESPR, we evaluated its functional role and revealed a link between expression patterns of NESPR and PHOX2B. Next to PHOX2B, 780 other genes were perturbed, including members of the noradrenergic and mesenchymal CRC. Reduced levels of NESPR also resulted in a decreased growth rate and subsequently apoptosis. The suspected mechanism through which NESPR operates involves the formation of chromatin structures to regulate PHOX2B expression. However, activity independent of PHOX2B has been identified through ChIRP sequencing, where motif enrichments of GATA3 and ISL1, two transcription factors of the noradrenergic CRC, were found. The results from these studies suggest that key neuroblastoma genes regulate a set of lincRNAs, which can play a role in neuroblastoma initiation and pathogenesis. Through experimental validation of one of the candidate genes, we confirmed its suspected functional activity in this pediatric malignancy. However, further experiments are essential to confirm functionality of the other lincRNAs contained in our core set.

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MLA
Rombaut, Dries. “LncRNAs as Novel Players in Neuroblastoma Tumor Biology.” 2019 : n. pag. Print.
APA
Rombaut, D. (2019). LncRNAs as novel players in neuroblastoma tumor biology. Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium.
Chicago author-date
Rombaut, Dries. 2019. “LncRNAs as Novel Players in Neuroblastoma Tumor Biology”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
Chicago author-date (all authors)
Rombaut, Dries. 2019. “LncRNAs as Novel Players in Neuroblastoma Tumor Biology”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
Vancouver
1.
Rombaut D. LncRNAs as novel players in neuroblastoma tumor biology. [Ghent, Belgium]: Ghent University. Faculty of Medicine and Health Sciences; 2019.
IEEE
[1]
D. Rombaut, “LncRNAs as novel players in neuroblastoma tumor biology,” Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium, 2019.
@phdthesis{8621675,
  abstract     = {In neuroblastoma, several protein coding genes are established as key players in the tumorigenesis and pathogenesis, such as ALK, MYCN and PHOX2B. These proteins regulate a plethora of other genes, however, little is known about their non-coding targets. Based on the combination of RNA sequencing data of 497 primary tumor samples and model systems for MYCN, ALK and PHOX2B, we could demonstrate that each of these key neuroblastoma genes regulate a core set of lincRNAs, some of which were associated with certain disease stages or survival. Furthermore, we analyzed the data to find lincRNAs that modulate the effect or are in charge of the regulation of these genes. Through a state-of-the-art computational workflow, various lincRNAs were identified as a functional member of the networks surrounding these key genes. Both approaches allowed us to establish a core set of lincRNAs with a potential implication in this pediatric malignancy. To confirm one of these results, we have experimentally validated our top candidate, a neuroblastoma specific lincRNA with an association with PHOX2B and overall survival. NESPR (NEuroblastoma Specific Phox2B Regulatory rna) is located in the genomic region of PHOX2B and is a member of the noradrenergic core regulatory circuit (CRC) in charge of neuroblastoma cell identity. Through antisense oligonucleotide (ASO) mediated downregulation of NESPR, we evaluated its functional role and revealed a link between expression patterns of NESPR and PHOX2B. Next to PHOX2B, 780 other genes were perturbed, including members of the noradrenergic and mesenchymal CRC. Reduced levels of NESPR also resulted in a decreased growth rate and subsequently apoptosis. The suspected mechanism through which NESPR operates involves the formation of chromatin structures to regulate PHOX2B expression. However, activity independent of PHOX2B has been identified through ChIRP sequencing, where motif enrichments of GATA3 and ISL1, two transcription factors of the noradrenergic CRC, were found. The results from these studies suggest that key neuroblastoma genes regulate a set of lincRNAs, which can play a role in neuroblastoma initiation and pathogenesis. Through experimental validation of one of the candidate genes, we confirmed its suspected functional activity in this pediatric malignancy. However, further experiments are essential to confirm functionality of the other lincRNAs contained in our core set.},
  author       = {Rombaut, Dries},
  language     = {eng},
  pages        = {VI, 170},
  publisher    = {Ghent University. Faculty of Medicine and Health Sciences},
  school       = {Ghent University},
  title        = {LncRNAs as novel players in neuroblastoma tumor biology},
  year         = {2019},
}