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See detailTranscriptional and epigenetic mechanisms underlying astrocyte identity
Pavlou, Maria Angeliki UL; Grandbarbe, Luc UL; Buckley, Noel et al

in Progress in Neurobiology (2018)

Astrocytes play a significant role in coordinating neural development and provide critical support for the function of the CNS. They possess important adaptation capacities that range from their ... [more ▼]

Astrocytes play a significant role in coordinating neural development and provide critical support for the function of the CNS. They possess important adaptation capacities that range from their transition towards reactive astrocytes to their ability to undergo reprogramming, thereby revealing their potential to retain latent features of neural progenitor cells. We propose that the mechanisms underlying reactive astrogliosis or astrocyte reprogramming provide an opportunity for initiating neuronal regeneration, a process that is notably reduced in the mammalian nervous system throughout evolution. Conversely, this plasticity may also affect normal astrocytic functions resulting in pathologies ranging from neurodevelopmental disorders to neurodegenerative diseases and brain tumors. We postulate that epigenetic mechanisms linking extrinsic cues and intrinsic transcriptional programs are key factors to maintain astrocyte identity and function, and critically, to control the balance of regenerative and degenerative activity. Here, we will review the main evidences supporting this concept. We propose that unravelling the epigenetic and transcriptional mechanisms underlying the acquisition of astrocyte identity and plasticity, as well as understanding how these processes are modulated by the local microenvironment under specific threatening or pathological conditions, may pave the way to new therapeutic avenues for several neurological disorders including neurodegenerative diseases and brain tumors of astrocytic lineage. [less ▲]

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See detailTranscriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+).
Hiller, Karsten UL

in Cell Death & Differentiation (2013)

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See detailTranscriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+).
Krug, AK.; Gutbier, S.; Zhao, L. et al

in Cell Death & Disease (2013)

Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network ... [more ▼]

Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network of responses, taking place in toxicanttreated cells before a point of no return is reached, is still little explored. We studied the effects of the model neurotoxicant 1-methyl-4-phenylpyridinium (MPPþ) by a combined metabolomics (mass spectrometry) and transcriptomics (microarrays and deep sequencing) approach to provide unbiased data on earliest cellular adaptations to stress. Neural precursor cells (LUHMES) were differentiated to homogeneous cultures of fully postmitotic human dopaminergic neurons, and then exposed to the mitochondrial respiratory chain inhibitor MPPþ (5 lM). At 18–24 h after treatment, intracellular ATP and mitochondrial integrity were still close to control levels, but pronounced transcriptome and metabolome changes were seen. Data on altered glucose flux, depletion of phosphocreatine and oxidative stress (e.g., methionine sulfoxide formation) confirmed the validity of the approach. New findings were related to nuclear paraspeckle depletion, as well as an early activation of branches of the transsulfuration pathway to increase glutathione. Bioinformatic analysis of our data identified the transcription factor ATF-4 as an upstream regulator of early responses. Findings on this signaling pathway and on adaptive increases of glutathione production were confirmed biochemically. Metabolic and transcriptional profiling contributed complementary information on multiple primary and secondary changes that contribute to the cellular response to MPPþ. Thus, combined ‘Omics’ analysis is a new unbiased approach to unravel earliest metabolic changes, whose balance decides on the final cell fate. [less ▲]

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See detailTranscriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more
Turner, Jonathan D.; Alt, Simone UL; Cao, Lei et al

in Biochemical Pharmacology (2010), 80(12), 1860-68

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See detailTranscriptional mechanisms underlying sensitization of peripheral sensory neurons by Granulocyte-/Granulocyte-macrophage colony stimulating factors.
Bali, Kiran Kumar; Venkataramani, Varun; Satagopam, Venkata UL et al

in Molecular pain (2013), 9(1), 48

BACKGROUND: Cancer-associated pain is a major cause of poor quality of life in cancer patients and is frequently resistant to conventional therapy. Recent studies indicate that some hematopoietic growth ... [more ▼]

BACKGROUND: Cancer-associated pain is a major cause of poor quality of life in cancer patients and is frequently resistant to conventional therapy. Recent studies indicate that some hematopoietic growth factors, namely granulocyte macrophage colony stimulating factor (GMCSF) and granulocyte colony stimulating factor (GCSF), are abundantly released in the tumor microenvironment and play a key role in regulating tumor-nerve interactions and tumor-associated pain by activating receptors on dorsal root ganglion (DRG) neurons. Moreover, these hematopoietic factors have been highly implicated in postsurgical pain, inflammatory pain and osteoarthritic pain. However, the molecular mechanisms via which G-/GMCSF bring about nociceptive sensitization and elicit pain are not known. RESULTS: In order to elucidate G-/GMCSF mediated transcriptional changes in the sensory neurons, we performed a comprehensive, genome-wide analysis of changes in the transcriptome of DRG neurons brought about by exposure to GMCSF or GCSF. We present complete information on regulated genes and validated profiling analyses and report novel regulatory networks and interaction maps revealed by detailed bioinformatics analyses. Amongst these, we validate calpain 2, matrix metalloproteinase 9 (MMP9) and a RhoGTPase Rac1 as well as Tumor necrosis factor alpha (TNFalpha) as transcriptional targets of G-/GMCSF and demonstrate the importance of MMP9 and Rac1 in GMCSF-induced nociceptor sensitization. CONCLUSION: With integrative approach of bioinformatics, in vivo pharmacology and behavioral analyses, our results not only indicate that transcriptional control by G-/GMCSF signaling regulates a variety of established pain modulators, but also uncover a large number of novel targets, paving the way for translational analyses in the context of pain disorders. [less ▲]

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See detailTranscriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR
Margue, Christiane UL; Bernasconi, Michele; Barr, Frederik et al

in Oncogene (2000), 19(25), 2921

The aberrant expression of the transcription factors PAX3 and PAX3/FKHR associated with rhabdomyosarcoma (RMS), solid tumors displaying muscle cell features, suggests that these proteins play an important ... [more ▼]

The aberrant expression of the transcription factors PAX3 and PAX3/FKHR associated with rhabdomyosarcoma (RMS), solid tumors displaying muscle cell features, suggests that these proteins play an important role in the pathogenesis of RMS. We could previously demonstrate that one of the oncogenic functions of PAX3 and PAX3/FKHR in RMS is protection from apoptosis. BCL-XL is a prominent anti-apoptotic protein present in normal skeletal muscle and RMS cells. In the present study, we establish that BCL-XL is transcriptionally modulated by PAX3 and PAX3/FKHR, since enhanced expression of both PAX proteins stimulates transcription of endogenous BCL-XL mRNA in a cell type specific manner. Further, we present evidence that both PAX3 and PAX3/FKHR can transcriptionally activate the Bcl-x gene promoter in cotransfection assays. Using electrophoretic mobility shift assays, an ATTA binding site for PAX3 and PAX3/FKHR could be localized in the upstream promoter region (position -42 to -39). Finally, ectopic overexpression of either PAX3, PAX3/FKHR or BCL-XL can rescue tumor cells from apoptosis induced by antisense treatment. These results suggest that at least part of the anti-apoptotic effect of PAX3 and PAX3/FKHR is mediated through direct transcriptional modulation of the prominent anti-apoptotic protein BCL-XL. [less ▲]

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See detailTranscriptional regulation of central carbon and energy metabolism in bacteria by redox responsive repressor Rex
Ravcheev, Dmitry UL; Li, Xiaoqing; Latif, Haythem et al

in Journal of Bacteriology (2012), 194(5), 1145-1157

Redox-sensing repressor Rex was previously implicated in the control of anaerobic respiration in response to the cellular NADH/NAD(+) levels in gram-positive bacteria. We utilized the comparative genomics ... [more ▼]

Redox-sensing repressor Rex was previously implicated in the control of anaerobic respiration in response to the cellular NADH/NAD(+) levels in gram-positive bacteria. We utilized the comparative genomics approach to infer candidate Rex-binding DNA motifs and assess the Rex regulon content in 119 genomes from 11 taxonomic groups. Both DNA-binding and NAD-sensing domains are broadly conserved in Rex orthologs identified in the phyla Firmicutes, Thermotogales, Actinobacteria, Chloroflexi, Deinococcus-Thermus, and Proteobacteria. The identified DNA-binding motifs showed significant conservation in these species, with the only exception detected in Clostridia, where the Rex motif deviates in two positions from the generalized consensus, TTGTGAANNNNTTCACAA. Comparative analysis of candidate Rex sites revealed remarkable variations in functional repertoires of candidate Rex-regulated genes in various microorganisms. Most of the reconstructed regulatory interactions are lineage specific, suggesting frequent events of gain and loss of regulator binding sites in the evolution of Rex regulons. We identified more than 50 novel Rex-regulated operons encoding functions that are essential for resumption of the NADH:NAD(+) balance. The novel functional role of Rex in the control of the central carbon metabolism and hydrogen production genes was validated by in vitro DNA binding assays using the TM0169 protein in the hydrogen-producing bacterium Thermotoga maritima. [less ▲]

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See detailTranscriptional regulation of the carbohydrate utilization network in Thermotoga maritima
Rodionov, Dmitry A.; Rodionova, Irina A.; Li et al

in Frontiers in Microbiology (2013), 4(244), 1-14

Hyperthermophilic bacteria from the Thermotogales lineage can produce hydrogen by fermenting a wide range of carbohydrates. Previous experimental studies identified a large fraction of genes committed to ... [more ▼]

Hyperthermophilic bacteria from the Thermotogales lineage can produce hydrogen by fermenting a wide range of carbohydrates. Previous experimental studies identified a large fraction of genes committed to carbohydrate degradation and utilization in the model bacterium Thermotoga maritima. Knowledge of these genes enabled comprehensive reconstruction of biochemical pathways comprising the carbohydrate utilization network. However, transcriptional factors (TFs) and regulatory mechanisms driving this network remained largely unknown. Here, we used an integrated approach based on comparative analysis of genomic and transcriptomic data for the reconstruction of the carbohydrate utilization regulatory networks in 11 Thermotogales genomes. We identified DNA-binding motifs and regulons for 19 orthologous TFs in the Thermotogales. The inferred regulatory network in T. maritima contains 181 genes encoding TFs, sugar catabolic enzymes and ABC-family transporters. In contrast to many previously described bacteria, a transcriptional regulation strategy of Thermotoga does not employ global regulatory factors. The reconstructed regulatory network in T. maritima was validated by gene expression profiling on a panel of mono- and disaccharides and by in vitro DNA-binding assays. The observed upregulation of genes involved in catabolism of pectin, trehalose, cellobiose, arabinose, rhamnose, xylose, glucose, galactose, and ribose showed a strong correlation with the UxaR, TreR, BglR, CelR, AraR, RhaR, XylR, GluR, GalR, and RbsR regulons. Ultimately, this study elucidated the transcriptional regulatory network and mechanisms controlling expression of carbohydrate utilization genes in T. maritima. In addition to improving the functional annotations of associated transporters and catabolic enzymes, this research provides novel insights into the evolution of regulatory networks in Thermotogales. [less ▲]

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See detailTranscriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia.
Saumet, Anne; Vetter, Guillaume; Bouttier, Manuella et al

in Blood (2009), 113(2), 412-21

Micro(mi)RNAs are small noncoding RNAs that orchestrate many key aspects of cell physiology and their deregulation is often linked to distinct diseases including cancer. Here, we studied the contribution ... [more ▼]

Micro(mi)RNAs are small noncoding RNAs that orchestrate many key aspects of cell physiology and their deregulation is often linked to distinct diseases including cancer. Here, we studied the contribution of miRNAs in a well-characterized human myeloid leukemia, acute promyelocytic leukemia (APL), targeted by retinoic acid and trioxide arsenic therapy. We identified several miRNAs transcriptionally repressed by the APL-associated PML-RAR oncogene which are released after treatment with all-trans retinoic acid. These coregulated miRNAs were found to control, in a coordinated manner, crucial pathways linked to leukemogenesis, such as HOX proteins and cell adhesion molecules whose expressions are thereby repressed by the chemotherapy. Thus, APL appears linked to transcriptional perturbation of miRNA genes, and clinical protocols able to successfully eradicate cancer cells may do so by restoring miRNA expression. The identification of abnormal miRNA biogenesis in cancer may therefore provide novel biomarkers and therapeutic targets in myeloid leukemias. [less ▲]

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See detailTranscriptional variations in the wider peritumoral tissue environment of pancreatic cancer
Bauer, Andrea S.; Nazarov, Petr V.; Giese, Nathalia A. et al

in International Journal of Cancer = Journal International du Cancer (2018), 142(5), 10101021

Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples ... [more ▼]

Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non-tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy-related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy-related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology. [less ▲]

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See detailTranscriptome of human foetal heart compared with cardiomyocytes from pluripotent stem cells
W. van den Berg, Cathelijne; Okawa, Satoshi UL; M. Chuva de Sousa Lopes, Susana et al

in Development (2015)

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See detailTranscriptome of human foetal heart compared with cardiomyocytes from pluripotent stem cells
del Sol Mesa, Antonio UL; Mummery, Christine

in Development (2015)

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See detailTranscriptome profiling data reveals Ubiquitin-Specific Peptidase 9 knockdown effects
Glaab, Enrico UL; Antony, Paul UL; Köglsberger, Sandra et al

in Data in Brief (2019), 25(1), 104130

Ubiquitin specific peptidase 9 (USP9) is a deubiquitinase encoded by a sex-linked gene with a Y-chromosomal form (USP9Y) and an X-chromosomal form (USP9X) that escapes X-inactivation. Since USP9 is a key ... [more ▼]

Ubiquitin specific peptidase 9 (USP9) is a deubiquitinase encoded by a sex-linked gene with a Y-chromosomal form (USP9Y) and an X-chromosomal form (USP9X) that escapes X-inactivation. Since USP9 is a key regulatory gene with sex-linked expression in the human brain, the gene may be of interest for researchers studying molecular gender differences and ubiquitin signaling in the brain. To assess the downstream effects of knocking down USP9X and USP9Y on a transcriptome-wide scale, we have conducted microarray profiling experiments using the human DU145 prostate cancer cell culture model, after confirming the robust expression of both USP9X and USP9Y in this model. By designing shRNA constructs for the specific knockdown of USP9X and the joint knockdown of USP9X and USP9Y, we have compared gene expression changes in both knockdowns to control conditions to infer potential shared and X- or Y-form specific alterations. Here, we provide details of the corresponding microarray profiling data, which has been deposited in the Gene Expression Omnibus database (GEO series accession number GSE79376). A biological interpretation of the data in the context of a potential involvement of USP9 in Alzheimer’s disease has previously been presented in Köglsberger et al. (2016). To facilitate the re-use and re-analysis of the data for other applications, e.g. the study of ubiquitin signaling and protein turnover control, and the regulation of molecular gender differences in the human brain and brain-related disorders, we provide a more in-depth discussion of the data properties, specifications and possible use cases. [less ▲]

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See detailTranscriptomic analyses of primary astrocytes under TNFα treatment
Birck, Cindy UL; Koncina, Eric UL; Heurtaux, Tony UL et al

in Genomics Data (2015), 7

Astrocytes, the most abundant glial cell population in the central nervous system, have important functional roles in the brain as blood brain barrier maintenance, synaptic transmission or intercellular ... [more ▼]

Astrocytes, the most abundant glial cell population in the central nervous system, have important functional roles in the brain as blood brain barrier maintenance, synaptic transmission or intercellular communications. Numerous studies suggested that astrocytes exhibit a functional and morphological high degree of plasticity. For example, following any brain injury, astrocytes become reactive and hypertrophic. This phenomenon, also called reactive gliosis, is characterized by a set of progressive gene expression and cellular changes. Interestingly, in this context, astrocytes can re-acquire neurogenic properties. It has been shown that astrocytes can undergo dedifferentiation upon injury and inflammation, and may re-acquire the potentiality of neural progenitors. To assess the effect of inflammation on astrocytes, primary mouse astrocytes were treated with tumor necrosis factor α (TNFα), one of the main pro-inflammatory cytokines. The strength of this study is that pure primary astrocytes were used. As microglia are highly reactive immune cells, we used a magnetic cell sorting separation (MACS) method to further obtain highly pure astrocyte cultures devoid of microglia. Here, we provide details of the microarray data, which have been deposited in the Gene Expression Omnibus (GEO) under the series accession number GSE73022. The analysis and interpretation of these data are included in Gabel et al. (2015). Analysis of gene expression indicated that the NFκB pathway-associated genes were induced after a TNFα treatment. We have shown that primary astrocytes devoid of microglia can respond to a TNFα treatment with the re-expression of genes implicated in the glial cell development. [less ▲]

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See detailTranscriptomics profiling of human SGBS adipogenesis
Galhardo, Mafalda Sofia UL; Sinkkonen, Lasse UL; Berninger, Philipp et al

in Genomics Data (2014), 2

Obesity is an ever-growing epidemic where tissue homeostasis is influenced by the differentiation of adipocytes that function in lipid metabolism, endocrine and inflammatory processes. While this ... [more ▼]

Obesity is an ever-growing epidemic where tissue homeostasis is influenced by the differentiation of adipocytes that function in lipid metabolism, endocrine and inflammatory processes. While this differentiation process has been well-characterized in mice, limited data is available from human cells. Applying microarray expression profiling in the human SGBS pre-adipocyte cell line, we identified genes with differential expression during differentiation in combination with constraint-based modeling of metabolic pathway activity. Here we describe the experimental design and quality controls in detail for the gene expression and related results published by Galhardo et al. in Nucleic Acids Research 2014 associated with the data uploaded to NCBI Gene Expression Omnibus (). [less ▲]

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See detailTranscultural Encounters: De- and Re-humanisation of the Worker in Multinational “Luxembourgish” Poetry, 1900-1940
Millim, Anne-Marie UL

in Les Cahiers luxembourgeois (2018), 1

This article contrasts the portrayal of the worker and his/her labour in French- and German-speaking book-poetry addressed to the Luxembourgish intelligentsia to the newspaper-poems consumed by the ... [more ▼]

This article contrasts the portrayal of the worker and his/her labour in French- and German-speaking book-poetry addressed to the Luxembourgish intelligentsia to the newspaper-poems consumed by the working-class readers of the social democratic organ Der Arme Teufel (1903-1929). It posits and illustrates that the attribution and simultaneous withdrawal of identity to the workers by bourgeois writers implies their incapacitation and disempowerment not only in financial terms, but also on a philosophico-literary level. In order to counteract the inscription of inferiority into cultural and literary history through aesthetic objectification, it seeks to reconstruct and include the workers’ perspective by shedding light on their transcultural consumption practices. Readers of Der Arme Teufel were presented with a wide selection of high-brow and amateur poetry from a multinational background, frequently, if not always, supporting the socialist cause. Analysing a selection of poems that depict the workers’ position in and their attitudes towards the factory system, this article proposes to widen the national literary canon to include the transcultural newspaper poetry consumed in Luxembourg in order to incorporate the multiplicity of literary expressions that formulated and shaped public consciousness. [less ▲]

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See detailA transdiagnostic dimensional approach towards a neuropsychological assessment for addiction: an international Delphi consensus study.
Yucel, Murat; Oldenhof, Erin; Ahmed, Serge et al

in Addiction (Abingdon, England) (2019), 114(6), 1095-1109

BACKGROUND: The U.S. National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness ... [more ▼]

BACKGROUND: The U.S. National Institutes of Mental Health Research Domain Criteria (RDoC) seek to stimulate research into biologically validated neuropsychological dimensions across mental illness symptoms and diagnoses. The RDoC framework comprises 39 functional constructs designed to be revised and refined, with the overall goal to improve diagnostic validity and treatments. This study aimed to reach a consensus among experts in the addiction field on the 'primary' RDoC constructs most relevant to substance and behavioural addictions. METHODS: Forty-four addiction experts were recruited from Australia, Asia, Europe and the Americas. The Delphi technique was used to determine a consensus as to the degree of importance of each construct in understanding the essential dimensions underpinning addictive behaviours. Expert opinions were canvassed online over three rounds (97% completion rate), with each consecutive round offering feedback for experts to review their opinions. RESULTS: Seven constructs were endorsed by >/=80% of experts as 'primary' to the understanding of addictive behaviour: five from the Positive Valence System (Reward Valuation, Expectancy, Action Selection, Reward Learning, Habit); one from the Cognitive Control System (Response Selection/Inhibition); and one expert-initiated construct (Compulsivity). These constructs were rated to be differentially related to stages of the addiction cycle, with some more closely linked to addiction onset, and others more to chronicity. Experts agreed that these neuropsychological dimensions apply across a range of addictions. CONCLUSIONS: The study offers a novel and neuropsychologically informed theoretical framework, as well as a cogent step forward to test transdiagnostic concepts in addiction research, with direct implications for assessment, diagnosis, staging of disorder, and treatment. [less ▲]

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