Long noncoding RNAs as a novel component of the Myc transcriptional network
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59480 | GEO | 2015/02/01
SECONDARY ACCESSION(S): PRJNA255406
REPOSITORIES: GEO
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2015-02-01 | E-GEOD-59480 | biostudies-arrayexpress
Project description:The impact of protein-coding genes on cancer onset and progression is a well-established paradigm in molecular oncology. Nevertheless, unveiling the contribution of the noncoding genes-including long noncoding RNAs (lncRNAs)-to tumorigenesis represents a great challenge for personalized medicine, since they (i) constitute the majority of the human genome, (ii) are essential and flexible regulators of gene expression and (iii) present all types of genomic alterations described for protein-coding genes. LncRNAs have been increasingly associated with cancer, their highly tissue- and cancer type-specific expression making them attractive candidates as both biomarkers and therapeutic targets. Medulloblastoma is one of the most common malignant pediatric brain tumors. Group 3 is the most aggressive subgroup, showing the highest rate of metastasis at diagnosis. Transcriptomics and reverse genetics approaches were combined to identify lncRNAs implicated in Group 3 Medulloblastoma biology. Here we present the first collection of lncRNAs dependent on the activity of the MYC oncogene, the major driver gene of Group 3 Medulloblastoma. We assessed the expression profile of selected lncRNAs in Group 3 primary tumors and functionally characterized these species. Overall, our data demonstrate the direct involvement of three lncRNAs in Medulloblastoma cancer cell phenotypes.
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Project description:The tumor-suppressor protein p53 is activated in response to numerous cellular stresses including DNA damage. p53 functions primarily as a sequence-specific transcription factor that controls the expression of hundreds of protein-coding genes and noncoding RNAs, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). While the role of protein-coding genes and miRNAs in mediating the effects of p53 has been extensively studied, the physiological function and molecular mechanisms by which p53-regulated lncRNAs act is beginning to be understood. In this review, we discuss recent studies on lncRNAs that are directly or indirectly regulated by p53 and how they contribute to the biological outcomes of p53 activation. WIREs RNA 2017, 8:e1410. doi: 10.1002/wrna.1410 For further resources related to this article, please visit the WIREs website.
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Project description:The transcription factor MYC is a proto-oncogene regulating cell proliferation, cell cycle, apoptosis and metabolism. The recent identification of MYC-regulated long noncoding RNAs (lncRNAs) expands our knowledge of the role of lncRNAs in MYC functions. Here, we identify MYC-repressed lncRNAs named MYCLo-4, -5 and -6 by comparing 3 categories of lncRNAs (downregulated in highly MYC-expressing colorectal cancer, up-regulated by MYC knockdown in HCT116, upregulated by MYC knockdown in RKO). The MYC-repressed MYCLos are implicated in MYC-modulated cell proliferation through cell cycle regulation. By screening cell cycle-related genes regulated by MYC and the MYC-repressed MYCLos, we identified the MYC-repressed gene GADD45A as a target gene of the MYC-repressed MYCLos such as MYCLo-4 and MYCLo-6.
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Project description:An increasing number of long noncoding RNAs (lncRNAs) have experimentally confirmed functions, yet little is known about their transcriptional dynamics and it is challenging to determine their regulatory effects. Here, we used allele-sensitive single-cell RNA sequencing to demonstrate that, compared to messenger RNAs, lncRNAs have twice as long duration between two transcriptional bursts. Additionally, we observed increased cell-to-cell variability in lncRNA expression due to lower frequency bursting producing larger numbers of RNA molecules. Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs with cell state-specific functions involved in cell cycle progression and apoptosis. Finally, we identified cis-functioning lncRNAs and showed that knockdown of these lncRNAs modulated the nearby protein-coding gene's transcriptional burst frequency or size. In summary, we identified distinct transcriptional regulation of lncRNAs and demonstrated a role for lncRNAs in the regulation of mRNA transcriptional bursting.
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Project description:Long noncoding RNAs (lncRNAs) are a class of molecules that impinge on the expression of protein-coding genes. Previous studies have suggested that the GAL cluster-associated lncRNAs of Saccharomyces cerevisiae repress expression of the protein-coding GAL genes. Herein, we demonstrate a previously unrecognized role for the GAL lncRNAs in activating gene expression. In yeast strains lacking the RNA helicase, DBP2, or the RNA decay enzyme, XRN1, we find that the GAL lncRNAs specifically accelerate gene expression from a prior repressive state. Furthermore, we provide evidence that the previously suggested repressive role is a result of specific mutant phenotypes, rather than a reflection of the normal, wild-type function of these noncoding RNAs. To shed light on the mechanism for lncRNA-dependent gene activation, we show that rapid induction of the protein-coding GAL genes is associated with faster recruitment of RNA polymerase II and reduced association of transcriptional repressors with GAL gene promoters. This suggests that the GAL lncRNAs enhance expression by derepressing the GAL genes. Consistently, the GAL lncRNAs enhance the kinetics of transcriptional induction, promoting faster expression of the protein-coding GAL genes upon the switch in carbon source. We suggest that the GAL lncRNAs poise inducible genes for rapid activation, enabling cells to more effectively trigger new transcriptional programs in response to cellular cues.
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Project description:Long noncoding RNAs (lncRNAs) are important regulators of cell fate, yet little is known about mechanisms controlling lncRNA expression. Here we show that transcription is quantitatively different for lncRNAs and mRNAs--as revealed by deficiency of Dicer (Dcr), a key RNase that generates microRNAs (miRNAs). Dcr loss in mouse embryonic stem cells led unexpectedly to decreased levels of hundreds of lncRNAs. The canonical Dgcr8-Dcr-miRNA pathway is required for robust lncRNA transcriptional initiation and elongation. Computational and genetic epistasis analyses demonstrated that Dcr activation of the oncogenic transcription factor cMyc is partly responsible for lncRNA expression. A quantitative metric of mRNA-lncRNA decoupling revealed that Dcr and cMyc differentially regulate lncRNAs versus mRNAs in diverse cell types and in vivo. Thus, numerous lncRNAs may be modulated as a class in development and disease, notably where Dcr and cMyc act.
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