Georges St Laurent

Publications (12)83.15 Total impact

• Article: On the Importance of Small Changes in RNA Expression.

  Georges St Laurent, Dmitry Shtokalo, Michael R Tackett, Zhaoqing Yang, Yuri Vyatkin, Patrice M Milos, Bernd Seilheimer, Timothy A McCaffrey, Philipp Kapranov
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  ABSTRACT: The analysis of the differential expression of genes has been the key goal of many molecular biology methods for decades and will remain with us for decades to come. It constitutesa fundamental resource at our disposal for determining the relationship between products of transcription, biology and disease. The completed genome sequencing of many common species allowed microarrays and RNA sequencing (RNAseq) to become major tools in Systems Biology. However, it is not uncommon to ignore transcripts with changes of less than a certain subjective threshold, typically around 2-3 fold, which we estimate happens in at least half of all experiments. Here we show that relatively low fold changes characterize a majority of the informative RNA changes actually occur with, with more than half of differentially expressed transcripts having a fold change of less than 2. We use highly quantitative single-molecule sequencing of total cellular RNA derived from a time course of inflammatory response, a process critical to a large number of diseases. Furthermore, we show that enrichment of biologically-relevant functions occurs even at very low fold changes in RNA levels. In addition, we show that most of the common statistical methods can reliably detect transcripts with low fold change when as few as 3 biological replicates are sequenced using single-molecule based RNAseq. In conclusion, given the prevalence of expression profiling in current research, the loss of data in half of all expression studies results in a significant, yet needless drain on the discovery process.
  Methods 04/2013; · 4.01 Impact Factor
• Article: Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts.

  Marco Magistri, Mohammad Ali Faghihi, Georges St Laurent, Claes Wahlestedt
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  ABSTRACT: In the decade following the publication of the Human Genome, noncoding RNAs (ncRNAs) have reshaped our understanding of the broad landscape of genome regulation. During this period, natural antisense transcripts (NATs), which are transcribed from the opposite strand of either protein or non-protein coding genes, have vaulted to prominence. Recent findings have shown that NATs can exert their regulatory functions by acting as epigenetic regulators of gene expression and chromatin remodeling. Here, we review recent work on the mechanisms of epigenetic modifications by NATs and their emerging role as master regulators of chromatin states. Unlike other long ncRNAs, antisense RNAs usually regulate their counterpart sense mRNA in cis by bridging epigenetic effectors and regulatory complexes at specific genomic loci. Understanding the broad range of effects of NATs will shed light on the complex mechanisms that regulate chromatin remodeling and gene expression in development and disease.
  Trends in Genetics 04/2012; 28(8):389-96. · 10.06 Impact Factor
• Source

  Available from: Gregory C Sartor

  Article: The Emerging Role of Non-Coding RNAs in Drug Addiction.

  Gregory C Sartor, Georges St Laurent, Claes Wahlestedt
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  ABSTRACT: Prolonged drug use causes long-lasting neuroadaptations in reward-related brain areas that contribute to addiction. Despite significant amount of research dedicated to understanding the underlying mechanisms of addiction, the molecular underpinnings remain unclear. At the same time, much of the pervasive transcription that encompasses the human genome occurs in the nervous system and contributes to its heterogeneity and complexity. Recent evidence suggests that non-coding RNAs (ncRNAs) play an important and dynamic role in transcriptional regulation, epigenetic signaling, stress response, and plasticity in the nervous system. Dysregulation of ncRNAs are thought to contribute to many, and perhaps all, neurological disorders, including addiction. Here, we review recent insights in the functional relevance of ncRNAs, including both microRNAs (miRNAs), and long non-coding RNAs, and then illustrate specific examples of ncRNA regulation in the context of drug addiction. We conclude that ncRNAs are importantly involved in the persistent neuroadaptations associated with addiction-related behaviors, and that therapies that target specific ncRNAs may represent new avenues for the treatment of drug addiction.
  Frontiers in genetics. 01/2012; 3:106.
• Source

  Available from: Mohammad Ali Faghihi

  Article: RNAi screen indicates widespread biological function for human natural antisense transcripts.

  Mohammad Ali Faghihi, Jannet Kocerha, Farzaneh Modarresi, Pär G Engström, Alistair M Chalk, Shaun P Brothers, Eric Koesema, Georges St Laurent, Claes Wahlestedt
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  ABSTRACT: Natural antisense transcripts represent a class of regulatory RNA molecules, which are characterized by their complementary sequence to another RNA transcript. Extensive sequencing efforts suggest that natural antisense transcripts are prevalent throughout the mammalian genome; however, their biological significance has not been well defined. We performed a loss-of-function RNA interference (RNAi) screen, which targeted 797 evolutionary conserved antisense transcripts, and found evidence for a regulatory role for a number of natural antisense transcripts. Specifically, we found that natural antisense transcripts for CCPG1 and RAPGEF3 may functionally disrupt signaling pathways and corresponding biological phenotypes, such as cell viability, either independently or in parallel with the corresponding sense transcript. Our results show that the large-scale siRNA screen can be applied to evaluate natural antisense transcript modulation of fundamental cellular events.
  PLoS ONE 01/2010; 5(10). · 4.09 Impact Factor
• Source

  Available from: Mohammad Ali Faghihi

  Article: Evidence for natural antisense transcript-mediated inhibition of microRNA function.

  Mohammad Ali Faghihi, Ming Zhang, Jia Huang, Farzaneh Modarresi, Marcel P Van der Brug, Michael A Nalls, Mark R Cookson, Georges St-Laurent, Claes Wahlestedt
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  ABSTRACT: MicroRNAs (miRNAs) have the potential to regulate diverse sets of mRNA targets. In addition, mammalian genomes contain numerous natural antisense transcripts, most of which appear to be non-protein-coding RNAs (ncRNAs). We have recently identified and characterized a highly conserved non-coding antisense transcript for beta-secretase-1 (BACE1), a critical enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript is markedly up-regulated in brain samples from Alzheimer's disease patients and promotes the stability of the (sense) BACE1 transcript. We report here that BACE1-antisense prevents miRNA-induced repression of BACE1 mRNA by masking the binding site for miR-485-5p. Indeed, miR-485-5p and BACE1-antisense compete for binding within the same region in the open reading frame of the BACE1 mRNA. We observed opposing effects of BACE1-antisense and miR-485-5p on BACE1 protein in vitro and showed that Locked Nucleic Acid-antimiR mediated knockdown of miR-485-5p as well as BACE1-antisense over-expression can prevent the miRNA-induced BACE1 suppression. We found that the expression of BACE1-antisense as well as miR-485-5p are dysregulated in RNA samples from Alzheimer's disease subjects compared to control individuals. Our data demonstrate an interface between two distinct groups of regulatory RNAs in the computation of BACE1 gene expression. Moreover, bioinformatics analyses revealed a theoretical basis for many other potential interactions between natural antisense transcripts and miRNAs at the binding sites of the latter.
  Genome biology 01/2010; 11(5):R56. · 6.63 Impact Factor
• Article: Non-coding RNA transcripts: sensors of neuronal stress, modulators of synaptic plasticity, and agents of change in the onset of Alzheimer's disease.

  Georges St Laurent, Mohammad Ali Faghihi, Claes Wahlestedt
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  ABSTRACT: Non-protein-coding RNAs (ncRNAs) play critical roles on many levels of cellular information processing and pervasive expression of ncRNAs in the nervous system could help explain brain complexity. NcRNAs are enriched in the central nervous system and are associated with specific neuroanatomical regions. Additionally, several recent publications have revealed an important role for deregulation of ncRNAs in various human neuropathologies, such as Alzheimer's disease, Parkinson's disease and Fragile X mental retardation. Herein, we summarize reports on functional ncRNA molecules involved in cellular stress response, particularly related to Alzheimer's disease. We conclude that ncRNAs have a prominent role in maintaining precise physiological levels of gene products directly implicated in Alzheimer's disease pathology.
  Neuroscience Letters 09/2009; 466(2):81-8. · 2.11 Impact Factor
• Article: Enhancing non-coding RNA information content with ADAR editing

  Georges St. Laurent, Yiannis A. Savva, Robert Reenan
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  ABSTRACT: The depth and complexity of the non-coding transcriptome in nervous system tissues provides a rich substrate for adenosine de-amination acting on RNA (ADAR). Non-coding RNAs (ncRNAs) serve diverse regulatory and computational functions, coupling signal flow from the environment to evolutionarily coded analog and digital information elements within the transcriptome. We present a perspective of ADARs interaction with the non-coding transcriptome as a computational matrix, enhancing the information processing power of the cell, adding flexibility, rapid response, and fine tuning to critical pathways. Dramatic increases in ADAR activity during stress response and inflammation result in powerful information processing events that change the functional state of the cell. This review examines the pathways and mechanisms of ADAR interaction with the non-coding transcriptome, and their functional consequences for information processing in nervous system tissues.
  Neuroscience Letters 09/2009; · 2.11 Impact Factor
• Source

  Available from: Timothy A McCaffrey

  Article: Cardiovascular inflammation and lesion cell apoptosis: a novel connection via the interferon-inducible immunoproteasome.

  Zhaoqing Yang, Dmitry Gagarin, Georges St Laurent, Neil Hammell, Ian Toma, Chien-An Hu, Ayaka Iwasa, Timothy A McCaffrey
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  ABSTRACT: Increasing evidence suggests that chronic inflammation contributes to atherogenesis, and that acute inflammatory events cause plaque rupture, thrombosis, and myocardial infarction. The present studies examined how inflammatory factors, such as interferon-gamma (IFNgamma), cause increased sensitivity to apoptosis in vascular lesion cells. Cells from the fibrous cap of human atherosclerotic lesions were sensitized by interferon-gamma (IFNgamma) to Fas-induced apoptosis, in a Bcl-X(L) reversible manner. Microarray profiling identified 72 INFgamma-induced transcripts with potential relevance to apoptosis. Half could be excluded because they were induced by IRF-1 overexpression, which did not sensitize to apoptosis. IFNgamma treatment strongly reduced Mcl-1, phospho-Bcl-2 (ser70), and phospho-Bcl-X(L) (ser62) protein levels. Candidate transcripts were modulated by siRNA, overexpression, or inhibitors to assess the effect on IFNgamma-induced Fas sensitivity. Surprisingly, siRNA knockdown of PSMB8 (LMP7), an "immunoproteasome" component, reversed IFNgamma-induced sensitivity to Fas ligation and prevented Fas/IFNgamma-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-X(L). Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-X(L) levels after IFNgamma treatment. Although critical for antigen presentation, the immunoproteasome appears to be a key link between inflammatory factors and the control of vascular cell apoptosis and may thus be an important factor in plaque rupture and myocardial infarction.
  Arteriosclerosis Thrombosis and Vascular Biology 06/2009; 29(8):1213-9. · 6.37 Impact Factor
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  Available from: Owen M Rennert

  Article: Molecular mechanism underlying differential apoptosis between human melanoma cell lines UACC903 and UACC903(+6) revealed by mitochondria-focused cDNA microarrays.

  Qiuyang Zhang, Jun Wu, Anhthu Nguyen, Bi-Dar Wang, Ping He, Georges St Laurent, Owen M Rennert, Yan A Su
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  ABSTRACT: Human malignant melanoma cell line UACC903 is resistant to apoptosis while chromosome 6-mediated suppressed cell line UACC903(+6) is sensitive. Here, we describe identification of differential molecular pathways underlying this difference. Using our recently developed mitochondria-focused cDNA microarrays, we identified 154 differentially expressed genes including proapoptotic (BAK1 [6p21.3], BCAP31, BNIP1, CASP3, CASP6, FAS, FDX1, FDXR, TNFSF10 and VDAC1) and antiapoptotic (BCL2L1, CLN3 and MCL1) genes. Expression of these pro- and anti-apoptotic genes was higher in UACC903(+6) than in UACC903 before UV treatment and was altered after UV treatment. qRT-PCR and Western blots validated microarray results. Our bioinformatic analysis mapped these genes to differential molecular pathways that predict resistance and sensitivity of UACC903 and UACC903(+6) to apoptosis respectively. The pathways were functionally confirmed by the FAS ligand-induced cell death and by siRNA knockdown of BAK1 protein. These results demonstrated the differential molecular pathways underlying survival and apoptosis of UACC903 and UACC903(+6) cell lines.
  Apoptosis 09/2008; 13(8):993-1004. · 4.07 Impact Factor
• Article: Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase.

  Mohammad Ali Faghihi, Farzaneh Modarresi, Ahmad M Khalil, Douglas E Wood, Barbara G Sahagan, Todd E Morgan, Caleb E Finch, Georges St Laurent, Paul J Kenny, Claes Wahlestedt
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  ABSTRACT: Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for beta-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-beta 1-42 (Abeta 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Abeta 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Abeta 1-42 in Alzheimer's disease.
  Nature medicine 08/2008; 14(7):723-30. · 27.14 Impact Factor
• Article: Noncoding RNAs: couplers of analog and digital information in nervous system function?

  Georges St Laurent, Claes Wahlestedt
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  ABSTRACT: The mammalian nervous system expresses numerous noncoding RNAs (ncRNAs). We propose that ncRNAs are capable of coupling the digital information universe of nucleic acids with the analog universe of cellular protein interactions. ncRNAs could contribute to the success of the organism's information processing in several ways. First, ncRNAs would allow for efficient coupling of energy with information, wherein less energy is required to represent and process more information, condensed in analog and digital form, into smaller spatial and temporal domains, ideal for the environments found in neural tissues. Second, ncRNAs would permit the rapid acquisition of information from the environment, along with the rapid flexible processing and elimination of that information when it is no longer necessary. Third, ncRNAs would facilitate accelerated evolution of an organism's information content and functional computational systems. This emerging panorama might open new dimensions of information processing in the nervous system.
  Trends in Neurosciences 01/2008; 30(12):612-21. · 14.23 Impact Factor
• Article: Meta-analysis of microarray results: challenges, opportunities, and recommendations for standardization.

  Patrick Cahan, Felicia Rovegno, Denise Mooney, John C Newman, Georges St Laurent, Timothy A McCaffrey
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  ABSTRACT: Microarray profiling of gene expression is a powerful tool for discovery, but the ability to manage and compare the resulting data can be problematic. Biological, experimental, and technical variations between studies of the same phenotype/phenomena create substantial differences in results. The application of conventional meta-analysis to raw microarray data is complicated by differences in the type of microarray used, gene nomenclatures, species, and analytical methods. An alternative approach to combining multiple microarray studies is to compare the published gene lists which result from the investigators' analyses of the raw data, as implemented in Lists of Lists Annotated (LOLA: www.lola.gwu.edu) and L2L (depts.washington.edu/l2l/). The present review considers both the potential value and the limitations of databasing and enabling the comparison of results from different microarray studies. Further, a major impediment to cross-study comparisons is the absence of a standard for reporting microarray study results. We propose a reporting standard: standard microarray results template (SMART), which will facilitate the integration of microarray studies.
  Gene 11/2007; 401(1-2):12-8. · 2.34 Impact Factor