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Search Results: 1 - 10 of 466358 matches for " Bassem A. Hassan "
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Fine-Tuning Enhancer Models to Predict Transcriptional Targets across Multiple Genomes
Stein Aerts, Jacques van Helden, Olivier Sand, Bassem A. Hassan
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0001115
Abstract: Networks of regulatory relations between transcription factors (TF) and their target genes (TG)- implemented through TF binding sites (TFBS)- are key features of biology. An idealized approach to solving such networks consists of starting from a consensus TFBS or a position weight matrix (PWM) to generate a high accuracy list of candidate TGs for biological validation. Developing and evaluating such approaches remains a formidable challenge in regulatory bioinformatics. We perform a benchmark study on 34 Drosophila TFs to assess existing TFBS and cis-regulatory module (CRM) detection methods, with a strong focus on the use of multiple genomes. Particularly, for CRM-modelling we investigate the addition of orthologous sites to a known PWM to construct phyloPWMs and we assess the added value of phylogenentic footprinting to predict contextual motifs around known TFBSs. For CRM-prediction, we compare motif conservation with network-level conservation approaches across multiple genomes. Choosing the optimal training and scoring strategies strongly enhances the performance of TG prediction for more than half of the tested TFs. Finally, we analyse a 35th TF, namely Eyeless, and find a significant overlap between predicted TGs and candidate TGs identified by microarray expression studies. In summary we identify several ways to optimize TF-specific TG predictions, some of which can be applied to all TFs, and others that can be applied only to particular TFs. The ability to model known TF-TG relations, together with the use of multiple genomes, results in a significant step forward in solving the architecture of gene regulatory networks.
The Atonal Proneural Transcription Factor Links Differentiation and Tumor Formation in Drosophila
Wouter Bossuyt,Natalie De Geest,Stein Aerts,Iris Leenaerts,Peter Marynen,Bassem A. Hassan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000040
Abstract: The acquisition of terminal cell fate and onset of differentiation are instructed by cell type–specific master control genes. Loss of differentiation is frequently observed during cancer progression, but the underlying causes and mechanisms remain poorly understood. We tested the hypothesis that master regulators of differentiation may be key regulators of tumor formation. Using loss- and gain-of-function analyses in Drosophila, we describe a critical anti-oncogenic function for the atonal transcription factor in the fly retina, where atonal instructs tissue differentiation. In the tumor context, atonal acts by regulating cell proliferation and death via the JNK stress response pathway. Combined with evidence that atonal's mammalian homolog, ATOH1, is a tumor suppressor gene, our data support a critical, evolutionarily conserved, function for ato in oncogenesis.
A Signaling Network for Patterning of Neuronal Connectivity in the Drosophila Brain
Mohammed Srahna,Maarten Leyssen,Ching Man Choi,Lee G. Fradkin,Jasprina N. Noordermeer,Bassem A. Hassan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0040348
Abstract: The precise number and pattern of axonal connections generated during brain development regulates animal behavior. Therefore, understanding how developmental signals interact to regulate axonal extension and retraction to achieve precise neuronal connectivity is a fundamental goal of neurobiology. We investigated this question in the developing adult brain of Drosophila and find that it is regulated by crosstalk between Wnt, fibroblast growth factor (FGF) receptor, and Jun N-terminal kinase (JNK) signaling, but independent of neuronal activity. The Rac1 GTPase integrates a Wnt-Frizzled-Disheveled axon-stabilizing signal and a Branchless (FGF)-Breathless (FGF receptor) axon-retracting signal to modulate JNK activity. JNK activity is necessary and sufficient for axon extension, whereas the antagonistic Wnt and FGF signals act to balance the extension and retraction required for the generation of the precise wiring pattern.
The Atonal Proneural Transcription Factor Links Differentiation and Tumor Formation in Drosophila
Wouter Bossuyt,Natalie De Geest,Stein Aerts,Iris Leenaerts,Peter Marynen,Bassem A Hassan
PLOS Biology , 2009, DOI: 10.1371/journal.pbio.1000040
Abstract: The acquisition of terminal cell fate and onset of differentiation are instructed by cell type–specific master control genes. Loss of differentiation is frequently observed during cancer progression, but the underlying causes and mechanisms remain poorly understood. We tested the hypothesis that master regulators of differentiation may be key regulators of tumor formation. Using loss- and gain-of-function analyses in Drosophila, we describe a critical anti-oncogenic function for the atonal transcription factor in the fly retina, where atonal instructs tissue differentiation. In the tumor context, atonal acts by regulating cell proliferation and death via the JNK stress response pathway. Combined with evidence that atonal's mammalian homolog, ATOH1, is a tumor suppressor gene, our data support a critical, evolutionarily conserved, function for ato in oncogenesis.
A Signaling Network for Patterning of Neuronal Connectivity in the Drosophila Brain
Mohammed Srahna,Maarten Leyssen,Ching Man Choi,Lee G Fradkin,Jasprina N Noordermeer,Bassem A Hassan
PLOS Biology , 2006, DOI: 10.1371/journal.pbio.0040348
Abstract: The precise number and pattern of axonal connections generated during brain development regulates animal behavior. Therefore, understanding how developmental signals interact to regulate axonal extension and retraction to achieve precise neuronal connectivity is a fundamental goal of neurobiology. We investigated this question in the developing adult brain of Drosophila and find that it is regulated by crosstalk between Wnt, fibroblast growth factor (FGF) receptor, and Jun N-terminal kinase (JNK) signaling, but independent of neuronal activity. The Rac1 GTPase integrates a Wnt-Frizzled-Disheveled axon-stabilizing signal and a Branchless (FGF)-Breathless (FGF receptor) axon-retracting signal to modulate JNK activity. JNK activity is necessary and sufficient for axon extension, whereas the antagonistic Wnt and FGF signals act to balance the extension and retraction required for the generation of the precise wiring pattern.
Robust Target Gene Discovery through Transcriptome Perturbations and Genome-Wide Enhancer Predictions in Drosophila Uncovers a Regulatory Basis for Sensory Specification
Stein Aerts,Xiao-Jiang Quan,Annelies Claeys,Marina Naval Sanchez,Phillip Tate,Jiekun Yan,Bassem A. Hassan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000435
Abstract: A comprehensive systems-level understanding of developmental programs requires the mapping of the underlying gene regulatory networks. While significant progress has been made in mapping a few such networks, almost all gene regulatory networks underlying cell-fate specification remain unknown and their discovery is significantly hampered by the paucity of generalized, in vivo validated tools of target gene and functional enhancer discovery. We combined genetic transcriptome perturbations and comprehensive computational analyses to identify a large cohort of target genes of the proneural and tumor suppressor factor Atonal, which specifies the switch from undifferentiated pluripotent cells to R8 photoreceptor neurons during larval development. Extensive in vivo validations of the predicted targets for the proneural factor Atonal demonstrate a 50% success rate of bona fide targets. Furthermore we show that these enhancers are functionally conserved by cloning orthologous enhancers from Drosophila ananassae and D. virilis in D. melanogaster. Finally, to investigate cis-regulatory cross-talk between Ato and other retinal differentiation transcription factors (TFs), we performed motif analyses and independent target predictions for Eyeless, Senseless, Suppressor of Hairless, Rough, and Glass. Our analyses show that cisTargetX identifies the correct motif from a set of coexpressed genes and accurately predicts target genes of individual TFs. The validated set of novel Ato targets exhibit functional enrichment of signaling molecules and a subset is predicted to be coregulated by other TFs within the retinal gene regulatory network.
Robust Target Gene Discovery through Transcriptome Perturbations and Genome-Wide Enhancer Predictions in Drosophila Uncovers a Regulatory Basis for Sensory Specification
Stein Aerts ,Xiao-Jiang Quan,Annelies Claeys,Marina Naval Sanchez,Phillip Tate,Jiekun Yan,Bassem A. Hassan
PLOS Biology , 2010, DOI: 10.1371/journal.pbio.1000435
Abstract: A comprehensive systems-level understanding of developmental programs requires the mapping of the underlying gene regulatory networks. While significant progress has been made in mapping a few such networks, almost all gene regulatory networks underlying cell-fate specification remain unknown and their discovery is significantly hampered by the paucity of generalized, in vivo validated tools of target gene and functional enhancer discovery. We combined genetic transcriptome perturbations and comprehensive computational analyses to identify a large cohort of target genes of the proneural and tumor suppressor factor Atonal, which specifies the switch from undifferentiated pluripotent cells to R8 photoreceptor neurons during larval development. Extensive in vivo validations of the predicted targets for the proneural factor Atonal demonstrate a 50% success rate of bona fide targets. Furthermore we show that these enhancers are functionally conserved by cloning orthologous enhancers from Drosophila ananassae and D. virilis in D. melanogaster. Finally, to investigate cis-regulatory cross-talk between Ato and other retinal differentiation transcription factors (TFs), we performed motif analyses and independent target predictions for Eyeless, Senseless, Suppressor of Hairless, Rough, and Glass. Our analyses show that cisTargetX identifies the correct motif from a set of coexpressed genes and accurately predicts target genes of individual TFs. The validated set of novel Ato targets exhibit functional enrichment of signaling molecules and a subset is predicted to be coregulated by other TFs within the retinal gene regulatory network.
Atonal homolog 1 Is a Tumor Suppressor Gene
Wouter Bossuyt,Avedis Kazanjian,Natalie De Geest,Sofie Van Kelst,Gert De Hertogh,Karel Geboes,Greg P. Boivin,Judith Luciani,Francois Fuks,Marinee Chuah,Thierry VandenDriessche,Peter Marynen,Jan Cools,Noah F. Shroyer,Bassem A. Hassan
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000039
Abstract: Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation.
Integrating Computational Biology and Forward Genetics in Drosophila
Stein Aerts equal contributor,Sven Vilain equal contributor,Shu Hu equal contributor,Leon-Charles Tranchevent equal contributor,Roland Barriot,Jiekun Yan,Yves Moreau,Bassem A. Hassan ,Xiao-Jiang Quan equal contributor
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000351
Abstract: Genetic screens are powerful methods for the discovery of gene–phenotype associations. However, a systems biology approach to genetics must leverage the massive amount of “omics” data to enhance the power and speed of functional gene discovery in vivo. Thus far, few computational methods for gene function prediction have been rigorously tested for their performance on a genome-wide scale in vivo. In this work, we demonstrate that integrating genome-wide computational gene prioritization with large-scale genetic screening is a powerful tool for functional gene discovery. To discover genes involved in neural development in Drosophila, we extend our strategy for the prioritization of human candidate disease genes to functional prioritization in Drosophila. We then integrate this prioritization strategy with a large-scale genetic screen for interactors of the proneural transcription factor Atonal using genomic deficiencies and mutant and RNAi collections. Using the prioritized genes validated in our genetic screen, we describe a novel genetic interaction network for Atonal. Lastly, we prioritize the whole Drosophila genome and identify candidate gene associations for ten receptor-signaling pathways. This novel database of prioritized pathway candidates, as well as a web application for functional prioritization in Drosophila, called Endeavour-HighFly, and the Atonal network, are publicly available resources. A systems genetics approach that combines the power of computational predictions with in vivo genetic screens strongly enhances the process of gene function and gene–gene association discovery.
Atonal homolog 1 Is a Tumor Suppressor Gene
Wouter Bossuyt equal contributor,Avedis Kazanjian equal contributor,Natalie De Geest,Sofie Van Kelst,Gert De Hertogh,Karel Geboes,Greg P Boivin,Judith Luciani,Francois Fuks,Marinee Chuah,Thierry VandenDriessche,Peter Marynen,Jan Cools,Noah F Shroyer ,Bassem A Hassan
PLOS Biology , 2009, DOI: 10.1371/journal.pbio.1000039
Abstract: Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation.
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