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Transcriptomic profiling of primary neuroblastomas revealsa high-risk tumor associated long noncoding RNA NBAT1, with functional roles in cell proliferation and neuronal differentiation.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-209582OAI: oai:DiVA.org:uu-209582DiVA: diva2:658636
Available from: 2013-10-22 Created: 2013-10-22 Last updated: 2014-01-23
In thesis
1. Regulatory Roles of Noncoding RNA in Development and Disease
Open this publication in new window or tab >>Regulatory Roles of Noncoding RNA in Development and Disease
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Long noncoding RNAs (lncRNAs) are being realized as important players in gene regulation and their misregulation has been considered as one of the underlying causes for tumor initiation and progression in many human pathologies. In the current thesis, I have addressed the functional role of lncRNAs in development and disease model systems.

Genomic imprinting is an epigenetic phenomenon by which subset of genes are expressed in a parent of origin-specific manner. The Kcnq1 imprinted locus is epigenetically regulated by Kcnq1ot1 lncRNA. Deletion of an 890bp region at the 5’ end of Kcnq1ot1 in mouse resulted in the loss of silencing of neighboring ubiqui-tously imprinted genes (UIGs). In addition, we observed loss of DNA methylation at the UIG promoters. We have shown that Kcnq1ot1 RNA establishes CpG methylation by interacting with DNMT1. To explore the stability of lncRNA mediated silencing pathways, we have conditionally deleted Kcnq1ot1 in the mouse in a stage and tissue-specific manner. We have shown that Kcnq1ot1 is continuously required for maintaining the silencing of UIGs, whereas the silencing of the placental im-printed genes is maintained in an RNA independent manner.  

To identify chromatin-associated lncRNA (CARs) on a genome-wide scale, we purified RNA from the sucrose gradient fractionated chromatin and subjected it to RNA sequencing. Our study has identified 141 intronic and 74 long intergenic CARs. Characterization of one of the CARs revealed that it regulates the expression of neighboring genes in cis by modulating the chromatin structure.  

We have explored the functional role of lncRNA in tumor progression and initiation by using pediatric neuroblastoma. By transcriptional profiling of low- and high-risk tumors, we have identified several lncRNAs differentially expressed between these subtypes. We report an uncharacterized RNA NBAT-1, expressed at lower levels in high-risk tumors relative to low-risk tumors.  Using neuroblastoma cell culture system, we demonstrated that NBAT-1 has anti-cell proliferative and anti-invasive properties. In addition, it promotes differentiation of neurons from undifferentiated neuroblastoma cell lines.  

In summary, by employing mouse genetics, cell culture based model system and expression profiling in tumors, we have uncovered new roles of lncRNA in gene regulation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 51 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 940
Noncoding RNA, Genomic Imprinting, Epigenetics, Neuroblastoma
National Category
Medical Genetics
urn:nbn:se:uu:diva-209596 (URN)978-91-554-8786-7 (ISBN)
Public defence
2013-12-04, Rudbecksalen, Rudbeck laboratory, Uppsala, 09:30 (English)
Available from: 2013-11-12 Created: 2013-10-22 Last updated: 2014-01-23

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