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Not "Junk" Anymore



The prevailing view has been that genetic information as something that is transmitted from the DNA via RNA to proteins. It is the proteins that perform all biological functions in cells. However, the protein coding portion of the genome makes up only 1.5% of the whole human DNA and the remaining 98.5 % was historically considered as "junk DNA" not producing any proteins. Development of high-resolution DNA and RNA sequencing technologies revealed that the so called Junk DNA give rise to tens of thousands of small and long noncoding RNA molecules. Long noncoding RNAs, which are more than 200 nucleotide in size, do not produce any proteins but have been shown to perform extremely important biological functions as RNA molecules, and their deregulation is reported to cause tumor development and progression.


Noncoding RNA in Development and Disease



Our lab has been interested in understanding how long noncoding RNAs control tumor initiation and progression, in addition to use them as potential biomarkers in diagnosis and therapy. We have been using neuroblastoma, a childhood cancer, as a model system to understand the functional role of long noncoding RNAs in cancer development and progression. By using new RNA sequencing technology on neuroblastoma tumors from a large group of Swedish children including both high-risk and low-risk neuroblastomas (108), we have identified several long noncoding RNAs that could have potential role in diagnosis and therapy. We are currently exploring the functional role of these differentially expressed long noncoding RNA in nuroblastoma progression and development.


Long non-coding RNAs in Neuroblastoma progression



NBAT-1 is differentially expressed between low and high-risk tumors. Its lower expression correlates with poor prognosis in neuroblastoma patients. It controls neuroblastoma progression through regulating pathways implicated in cellular proliferation, invasion and neuronal differentiation.

Model explaining the tumor suppressor and neuronal differentiation properties of NBAT-1. NBAT-1 functional interaction with EZH2, a member of PRC2 complex, controls tumor progression by suppressing protumor genes such as SOX9, VCAN, and OSMR via regulating chromatin structure. On the other hand, NBAT-1 promotes neuronal lineage commitment by suppressing NRSF/REST by interacting with an unknown neuronal-linage-specific transcriptional repressor. The NBAT-1/EZH2 interaction has no functional role in the repression of NRSF/REST.


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Kcnq1ot1 LncRNA



Kcnq1ot1 long noncoding RNA, a chromatin regulating RNA, controls imprinted expression of the neighbouring genes through modulating the chromatin structure of their promoter in cis.

We have shown that Kcnq1ot1 noncoding RNA mediates the transcriptional silencing of both ubiquitous and placentally imprinted genes only on the paternal chromosome but not on the maternal chromosome due to silencing of the Kcnq1ot1 promoter by DNA methylation on the maternal chromosome. Kcnq1ot1 RNA does the silencing of multiple imprinted genes by interacting with DNA and chromatin modifying enzymes such as DNMT and G9a, PRC2 complex members Ezh2 and Suz12 and specifically targeting them to the promoters of imprinted genes within the one mega-base Kcnq1 domain, resulting in the formation of higher order repressive chromatin structure devoid of RNA polymerase II. This Kcnq1ot1 RNA mediated targeting of DNA and chromatin modifying enzymes over the imprinted promoters in the Kcnq1 domain establishes a multilayered silencing pathway, and involves the targeting of silenced genes to perinucleolar space, enriched with the repressive transcriptional machinery such as Ezh2.


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