Publications by authors named "Jesper Maag"

22 Publications

  • Page 1 of 1

A gene-environment-induced epigenetic program initiates tumorigenesis.

Nature 2021 02 3;590(7847):642-648. Epub 2021 Feb 3.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tissue damage increases the risk of cancer through poorly understood mechanisms. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.
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http://dx.doi.org/10.1038/s41586-020-03147-xDOI Listing
February 2021

SWI/SNF complex mutations promote thyroid tumor progression and insensitivity to redifferentiation therapies.

Cancer Discov 2020 Dec 14. Epub 2020 Dec 14.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center

Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of Arid1a, Arid2 or Smarcb1 in mouse BrafV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared to normal thyrocytes, BrafV600E-mutant mouse PTCs have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual Swi/Snf subunits in Braf tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor-based redifferentiation therapies.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0735DOI Listing
December 2020

FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer.

Cancer Cell 2020 10 3;38(4):534-550.e9. Epub 2020 Sep 3.

Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third β strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.
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http://dx.doi.org/10.1016/j.ccell.2020.08.003DOI Listing
October 2020

PRMT5 Inhibition Modulates E2F1 Methylation and Gene-Regulatory Networks Leading to Therapeutic Efficacy in JAK2-Mutant MPN.

Cancer Discov 2020 Nov 15;10(11):1742-1757. Epub 2020 Jul 15.

Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation . PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2 polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPL model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN. SIGNIFICANCE: Expression of PRMT5 and E2F targets is increased in JAK2 MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2/MPL MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642059PMC
November 2020

Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma.

Nat Genet 2020 01 16;52(1):29-34. Epub 2019 Dec 16.

Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.
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http://dx.doi.org/10.1038/s41588-019-0547-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008131PMC
January 2020

The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35.

Nat Commun 2019 11 5;10(1):5026. Epub 2019 Nov 5.

Children's Cancer Institute Australia for Medical Research, Randwick, NSW, 2031, Australia.

The majority of patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most over-expressed in MYCN-amplified, compared with MYCN-non-amplified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets.
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http://dx.doi.org/10.1038/s41467-019-12971-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831662PMC
November 2019

gganatogram: An R package for modular visualisation of anatograms and tissues based on ggplot2.

Authors:
Jesper L V Maag

F1000Res 2018 28;7:1576. Epub 2018 Sep 28.

Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.

Displaying data onto anatomical structures is a convenient technique to quickly observe tissue related information. However, drawing tissues is a complex task that requires both expertise in anatomy and the arts. While web based applications exist for displaying gene expression on anatograms, other non-genetic disciplines lack similar tools. Moreover, web based tools often lack the modularity associated with packages in programming languages, such as R. Here I present gganatogram, an R package used to plot modular species anatograms based on a combination of the graphical grammar of ggplot2 and the publicly available anatograms from the Expression Atlas. This combination allows for quick and easy, modular, and reproducible generation of anatograms. Using only one command and a data frame with tissue name, group, colour, and  value, this tool enables the user to visualise specific human and mouse tissues with desired colours, grouped by a variable, or displaying a desired value, such as gene-expression, pharmacokinetics, or bacterial load across selected tissues. gganatogram consists of 5 highly annotated organisms, male/female human/mouse, and a cell anatogram. It further consists of 24 other less annotated organisms from the animal and plant kingdom. I hope that this tool will be useful by the wider community in biological sciences. Community members are welcome to submit additional anatograms, which can be incorporated into the package. A stable version gganatogram has been deposited to neuroconductor, and a development version can be found on  github/jespermaag/gganatogram. An interactive shiny app of gganatogram can be found on  https://jespermaag.shinyapps.io/gganatogram/, which allows for non-R users to create anatograms.
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http://dx.doi.org/10.12688/f1000research.16409.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208569PMC
September 2018

Targeting the CALR interactome in myeloproliferative neoplasms.

JCI Insight 2018 11 15;3(22). Epub 2018 Nov 15.

Human Oncology and Pathogenesis Program.

Mutations in the ER chaperone calreticulin (CALR) are common in myeloproliferative neoplasm (MPN) patients, activate the thrombopoietin receptor (MPL), and mediate constitutive JAK/STAT signaling. The mechanisms by which CALR mutations cause myeloid transformation are incompletely defined. We used mass spectrometry proteomics to identify CALR-mutant interacting proteins. Mutant CALR caused mislocalization of binding partners and increased recruitment of FLI1, ERP57, and CALR to the MPL promoter to enhance transcription. Consistent with a critical role for CALR-mediated JAK/STAT activation, we confirmed the efficacy of JAK2 inhibition on CALR-mutant cells in vitro and in vivo. Due to the altered interactome induced by CALR mutations, we hypothesized that CALR-mutant MPNs may be vulnerable to disruption of aberrant CALR protein complexes. A synthetic peptide designed to competitively inhibit the carboxy terminal of CALR specifically abrogated MPL/JAK/STAT signaling in cell lines and primary samples and improved the efficacy of JAK kinase inhibitors. These findings reveal what to our knowledge is a novel potential therapeutic approach for patients with CALR-mutant MPN.
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http://dx.doi.org/10.1172/jci.insight.122703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302938PMC
November 2018

CCR6 Defines Memory B Cell Precursors in Mouse and Human Germinal Centers, Revealing Light-Zone Location and Predominant Low Antigen Affinity.

Immunity 2017 12;47(6):1142-1153.e4

Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; St. Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW 2010, Australia. Electronic address:

Memory B cells (MBCs) and plasma cells (PCs) constitute the two cellular outputs of germinal center (GC) responses that together facilitate long-term humoral immunity. Although expression of the transcription factor BLIMP-1 identifies cells undergoing PC differentiation, no such marker exists for cells committed to the MBC lineage. Here, we report that the chemokine receptor CCR6 uniquely marks MBC precursors in both mouse and human GCs. CCR6 GC B cells were highly enriched within the GC light zone (LZ), were the most quiescent of all GC B cells, exhibited a cell-surface phenotype and gene expression signature indicative of an MBC transition, and possessed the augmented response characteristics of MBCs. MBC precursors within the GC LZ predominantly possessed a low affinity for antigen but also included cells from within the high-affinity pool. These data indicate a fundamental dichotomy between the processes that drive MBC and PC differentiation during GC responses.
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http://dx.doi.org/10.1016/j.immuni.2017.11.022DOI Listing
December 2017

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing.

Mol Cancer Res 2017 11 27;15(11):1558-1569. Epub 2017 Jul 27.

Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia.

Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence of any cancer, along with poor five-year survival rates. Barrett's esophagus (BE) is the main risk factor for EAC; however, the mechanisms driving EAC development remain poorly understood. Here, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on premalignant and malignant Barrett's tissues to better understand this disease. Machine-learning and network analysis methods were applied to discover novel driver genes for EAC development. Identified gene expression signatures for the distinction of EAC from BE were validated in separate datasets. An extensive analysis of the noncoding RNA (ncRNA) landscape was performed to determine the involvement of novel transcriptomic elements in Barrett's disease and EAC. Finally, transcriptomic mutational investigation of genes that are recurrently mutated in EAC was performed. Through these approaches, novel driver genes were discovered for EAC, which involved key cell cycle and DNA repair genes, such as BRCA1 and PRKDC. A novel 4-gene signature (CTSL, COL17A1, KLF4, and E2F3) was identified, externally validated, and shown to provide excellent distinction of EAC from BE. Furthermore, expression changes were observed in 685 long noncoding RNAs (lncRNA) and a systematic dysregulation of repeat elements across different stages of Barrett's disease, with wide-ranging downregulation of Alu elements in EAC. Mutational investigation revealed distinct pathways activated between EAC tissues with or without TP53 mutations compared with Barrett's disease. In summary, transcriptome sequencing revealed altered expression of numerous novel elements, processes, and networks in EAC and premalignant BE. This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0332DOI Listing
November 2017

Benchmarking of RNA-sequencing analysis workflows using whole-transcriptome RT-qPCR expression data.

Sci Rep 2017 05 8;7(1):1559. Epub 2017 May 8.

Center for Medical Genetics, Ghent University, Ghent, Belgium.

RNA-sequencing has become the gold standard for whole-transcriptome gene expression quantification. Multiple algorithms have been developed to derive gene counts from sequencing reads. While a number of benchmarking studies have been conducted, the question remains how individual methods perform at accurately quantifying gene expression levels from RNA-sequencing reads. We performed an independent benchmarking study using RNA-sequencing data from the well established MAQCA and MAQCB reference samples. RNA-sequencing reads were processed using five workflows (Tophat-HTSeq, Tophat-Cufflinks, STAR-HTSeq, Kallisto and Salmon) and resulting gene expression measurements were compared to expression data generated by wet-lab validated qPCR assays for all protein coding genes. All methods showed high gene expression correlations with qPCR data. When comparing gene expression fold changes between MAQCA and MAQCB samples, about 85% of the genes showed consistent results between RNA-sequencing and qPCR data. Of note, each method revealed a small but specific gene set with inconsistent expression measurements. A significant proportion of these method-specific inconsistent genes were reproducibly identified in independent datasets. These genes were typically smaller, had fewer exons, and were lower expressed compared to genes with consistent expression measurements. We propose that careful validation is warranted when evaluating RNA-seq based expression profiles for this specific gene set.
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http://dx.doi.org/10.1038/s41598-017-01617-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431503PMC
May 2017

Widespread promoter methylation of synaptic plasticity genes in long-term potentiation in the adult brain in vivo.

BMC Genomics 2017 03 23;18(1):250. Epub 2017 Mar 23.

Division of Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, Australia.

Background: DNA methylation is a key modulator of gene expression in mammalian development and cellular differentiation, including neurons. To date, the role of DNA modifications in long-term potentiation (LTP) has not been explored.

Results: To investigate the occurrence of DNA methylation changes in LTP, we undertook the first detailed study to describe the methylation status of all known LTP-associated genes during LTP induction in the dentate gyrus of live rats. Using a methylated DNA immunoprecipitation (MeDIP)-array, together with previously published matched RNA-seq and public histone modification data, we discover widespread changes in methylation status of LTP-genes. We further show that the expression of many LTP-genes is correlated with their methylation status. We show that these correlated genes are enriched for RNA-processing, active histone marks, and specific transcription factors. These data reveal that the synaptic activity-evoked methylation changes correlates with pre-existing activation of the chromatin landscape. Finally, we show that methylation of Brain-derived neurotrophic factor (Bdnf) CpG-islands correlates with isoform switching from transcripts containing exon IV to exon I.

Conclusions: Together, these data provide the first evidence of widespread regulation of methylation status in LTP-associated genes.
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http://dx.doi.org/10.1186/s12864-017-3621-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364592PMC
March 2017

The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states.

Sci Rep 2017 01 5;7:40127. Epub 2017 Jan 5.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.

Despite their abundance, the molecular functions of long non-coding RNAs in mammalian nervous systems remain poorly understood. Here we show that the long non-coding RNA, NEAT1, directly modulates neuronal excitability and is associated with pathological seizure states. Specifically, NEAT1 is dynamically regulated by neuronal activity in vitro and in vivo, binds epilepsy-associated potassium channel-interacting proteins including KCNAB2 and KCNIP1, and induces a neuronal hyper-potentiation phenotype in iPSC-derived human cortical neurons following antisense oligonucleotide knockdown. Next generation sequencing reveals a strong association of NEAT1 with increased ion channel gene expression upon activation of iPSC-derived neurons following NEAT1 knockdown. Furthermore, we show that while NEAT1 is acutely down-regulated in response to neuronal activity, repeated stimulation results in NEAT1 becoming chronically unresponsive in independent in vivo rat model systems relevant to temporal lobe epilepsy. We extended previous studies showing increased NEAT1 expression in resected cortical tissue from high spiking regions of patients suffering from intractable seizures. Our results indicate a role for NEAT1 in modulating human neuronal activity and suggest a novel mechanistic link between an activity-dependent long non-coding RNA and epilepsy.
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http://dx.doi.org/10.1038/srep40127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214838PMC
January 2017

CD151 Gene and Protein Expression Provides Independent Prognostic Information for Patients with Adenocarcinoma of the Esophagus and Gastroesophageal Junction Treated by Esophagectomy.

Ann Surg Oncol 2016 12 30;23(Suppl 5):746-754. Epub 2016 Aug 30.

Gastroesophageal Cancer Program, St. Vincent's Centre for Applied Medical Research, Sydney, Australia.

Background: Esophageal and gastroesophageal junctional (GEJ) adenocarcinoma is one of the most fatal cancers and has the fastest rising incidence rate of all cancers. Identification of biomarkers is needed to tailor treatments to each patient's tumor biology and prognosis.

Methods: Gene expression profiling was performed in a test cohort of 80 chemoradiotherapy (CRTx)-naïve patients with external validation in a separate cohort of 62 CRTx-naïve patients and 169 patients with advanced-stage disease treated with CRTx.

Results: As a novel prognostic biomarker after external validation, CD151 showed promise. Patients exhibiting high levels of CD151 (≥median) had a longer median overall survival than patients with low CD151 tumor levels (median not reached vs. 30.9 months; p = 0.01). This effect persisted in a multivariable Cox-regression model with adjustment for tumor stage [adjusted hazard ratio (aHR), 0.33; 95 % confidence interval (CI), 0.14-0.78; p = 0.01] and was further corroborated through immunohistochemical analysis (aHR, 0.22; 95 % CI, 0.08-0.59; p = 0.003). This effect was not found in the separate cohort of CRTx-exposed patients.

Conclusion: Tumoral expression levels of CD151 may provide independent prognostic information not gained by conventional staging of patients with esophageal and GEJ adenocarcinoma treated by esophagectomy alone.
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http://dx.doi.org/10.1245/s10434-016-5504-9DOI Listing
December 2016

Corrigendum: Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity.

Front Neurosci 2016 27;10:354. Epub 2016 Jul 27.

Department of Biomedicine and K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen Bergen, Norway.

[This corrects the article on p. 351 in vol. 9, PMID: 26483626.].
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http://dx.doi.org/10.3389/fnins.2016.00354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961693PMC
July 2016

Long noncoding RNAs in cancer: mechanisms of action and technological advancements.

Mol Cancer 2016 05 27;15(1):43. Epub 2016 May 27.

Genome Informatics, Genomics & Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia.

The previous decade has seen long non-coding RNAs (lncRNAs) rise from obscurity to being defined as a category of genetic elements, leaving its mark on the field of cancer biology. With the current number of curated lncRNAs increasing by 10,000 in the last five years, the field is moving from annotation of lncRNA expression in various tumours to understanding their importance in the key cancer signalling networks and characteristic behaviours. Here, we summarize the previously identified as well as recently discovered mechanisms of lncRNA function and their roles in the hallmarks of cancer. Furthermore, we identify novel technologies for investigation of lncRNA properties and their function in carcinogenesis, which will be important for their translation to the clinic as novel biomarkers and therapeutic targets.
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http://dx.doi.org/10.1186/s12943-016-0530-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884374PMC
May 2016

Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity.

Front Neurosci 2015 1;9:351. Epub 2015 Oct 1.

Department of Biomedicine and K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen Bergen, Norway.

Long-term potentiation (LTP) of synaptic transmission is recognized as a cellular mechanism for learning and memory storage. Although de novo gene transcription is known to be required in the formation of stable LTP, the molecular mechanisms underlying synaptic plasticity remain elusive. Noncoding RNAs have emerged as major regulatory molecules that are abundantly and specifically expressed in the mammalian brain. By combining RNA-seq analysis with LTP induction in the dentate gyrus of live rats, we provide the first global transcriptomic analysis of synaptic plasticity in the adult brain. Expression profiles of mRNAs and long noncoding RNAs (lncRNAs) were obtained at 30 min, 2 and 5 h after high-frequency stimulation of the perforant pathway. The temporal analysis revealed dynamic expression profiles of lncRNAs with many positively, and highly, correlated to protein-coding genes with known roles in synaptic plasticity, suggesting their possible involvement in LTP. In light of observations suggesting a role for retrotransposons in brain function, we examined the expression of various classes of repeat elements. Our analysis identifies dynamic regulation of LINE1 and SINE retrotransposons, and extensive regulation of tRNA. These experiments reveal a hitherto unknown complexity of gene expression in long-term synaptic plasticity involving the dynamic regulation of lncRNAs and repeat elements. These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity in both the healthy brain and in neurodegenerative and neuropsychiatric disorders.
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http://dx.doi.org/10.3389/fnins.2015.00351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589673PMC
October 2015

lncRNAdb v2.0: expanding the reference database for functional long noncoding RNAs.

Nucleic Acids Res 2015 Jan 20;43(Database issue):D168-73. Epub 2014 Oct 20.

Garvan Institute of Medical Research, 384 Victoria Street, Sydney, NSW 2010, Australia St Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia

Despite the prevalence of long noncoding RNA (lncRNA) genes in eukaryotic genomes, only a small proportion have been examined for biological function. lncRNAdb, available at http://lncrnadb.org, provides users with a comprehensive, manually curated reference database of 287 eukaryotic lncRNAs that have been described independently in the scientific literature. In addition to capturing a great proportion of the recent literature describing functions for individual lncRNAs, lncRNAdb now offers an improved user interface enabling greater accessibility to sequence information, expression data and the literature. The new features in lncRNAdb include the integration of Illumina Body Atlas expression profiles, nucleotide sequence information, a BLAST search tool and easy export of content via direct download or a REST API. lncRNAdb is now endorsed by RNAcentral and is in compliance with the International Nucleotide Sequence Database Collaboration.
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http://dx.doi.org/10.1093/nar/gku988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384040PMC
January 2015

Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro.

Cell Mol Neurobiol 2014 Jan 13;34(1):31-42. Epub 2013 Sep 13.

Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.

Cannabinoid (CB) ligands have demonstrated neuroprotective properties. In this study we compared the effects of a diverse set of CB ligands against β amyloid-mediated neuronal toxicity and activated microglial-conditioned media-based neurotoxicity in vitro, and compared this with a capacity to directly alter β amyloid (Aβ) fibril or aggregate formation. Neuroblastoma (SH-SY5Y) cells were exposed to Aβ1-42 directly or microglial (BV-2 cells) conditioned media activated with lipopolysaccharide (LPS) in the presence of the CB1 receptor-selective agonist ACEA, CB2 receptor-selective agonist JWH-015, phytocannabinoids Δ(9)-THC and cannabidiol (CBD), the endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide or putative GPR18/GPR55 ligands O-1602 and abnormal-cannabidiol (Abn-CBD). TNF-α and nitrite production was measured in BV-2 cells to compare activation via LPS or albumin with Aβ1-42. Aβ1-42 evoked a concentration-dependent loss of cell viability in SH-SY5Y cells but negligible TNF-α and nitrite production in BV-2 cells compared to albumin or LPS. Both albumin and LPS-activated BV-2 conditioned media significantly reduced neuronal cell viability but were directly innocuous to SH-SY5Y cells. Of those CB ligands tested, only 2-AG and CBD were directly protective against Aβ-evoked SH-SY5Y cell viability, whereas JWH-015, THC, CBD, Abn-CBD and O-1602 all protected SH-SY5Y cells from BV-2 conditioned media activated via LPS. While CB ligands variably altered the morphology of Aβ fibrils and aggregates, there was no clear correlation between effects on Aβ morphology and neuroprotective actions. These findings indicate a neuroprotective action of CB ligands via actions at microglial and neuronal cells.
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http://dx.doi.org/10.1007/s10571-013-9984-xDOI Listing
January 2014

Dietary polyphenol-derived protection against neurotoxic β-amyloid protein: from molecular to clinical.

Food Funct 2012 Dec;3(12):1242-50

Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, South Australia.

Polyphenolic compounds derived mainly from plant products have demonstrated neuroprotective properties in a number of experimental settings. Such protective effects have often been ascribed to antioxidant capacity, but specific augmentation of other cellular defences and direct interactions with neurotoxic proteins have also been demonstrated. With an emphasis on neurodegenerative conditions, such as Alzheimer's disease, we highlight recent findings on the neuroprotection ascribed to bioactive polyphenols capable of directly interfering with the Alzheimer's disease hallmark toxic β-amyloid protein (Aβ), thereby inhibiting fibril and aggregate formation. This includes compounds such as the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) and the phytoalexin resveratrol. Targeted studies on the biomolecular interactions between dietary polyphenolics and Aβ have not only improved our understanding of the pathogenic role of β-amyloid, but also offer fundamentally novel treatment options for Alzheimer's disease and potentially other amyloidoses.
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http://dx.doi.org/10.1039/c2fo30075cDOI Listing
December 2012

Contrasting protective effects of cannabinoids against oxidative stress and amyloid-β evoked neurotoxicity in vitro.

Neurotoxicology 2012 Jan 3;33(1):138-46. Epub 2012 Jan 3.

Discipline of Pharmacology, School of Medical Sciences, Faculty of Health Sciences, The University of Adelaide, SA, Australia.

Cannabinoids have been widely reported to have neuroprotective properties in vitro and in vivo. In this study we compared the effects of CB1 and CB2 receptor-selective ligands, the endocannabinoid anandamide and the phytocannabinoid cannabidiol, against oxidative stress and the toxic hallmark Alzheimer's protein, β-amyloid (Aβ) in neuronal cell lines. PC12 or SH-SY5Y cells were selectively exposed to either hydrogen peroxide, tert-butyl hydroperoxide or Aβ, alone or in the presence of the CB1 specific agonist arachidonyl-2'-chloroethylamide (ACEA), CB2 specific agonist JWH-015, anandamide or cannabidiol. Cannabidiol improved cell viability in response to tert-butyl hydroperoxide in PC12 and SH-SY5Y cells, while hydrogen peroxide-mediated toxicity was unaffected by cannabidiol pretreatment. Aβ exposure evoked a loss of cell viability in PC12 cells. Of the cannabinoids tested, only anandamide was able to inhibit Aβ-evoked neurotoxicity. ACEA had no effect on Aβ-evoked neurotoxicity, suggesting a CB1 receptor-independent effect of anandamide. JWH-015 pretreatment was also without protective influence on PC12 cells from either pro-oxidant or Aβ exposure. None of the cannabinoids directly inhibited or disrupted preformed Aβ fibrils and aggregates. In conclusion, the endocannabinoid anandamide protects neuronal cells from Aβ exposure via a pathway unrelated to CB1 or CB2 receptor activation. The protective effect of cannabidiol against oxidative stress does not confer protection against Aβ exposure, suggesting divergent pathways for neuroprotection of these two cannabinoids.
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http://dx.doi.org/10.1016/j.neuro.2011.12.015DOI Listing
January 2012