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  • 1
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    Global intron retention mediated gene regulation during CD4+ T cell activation (2016)
    Oxford University Press
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    Publication Date: 2016-08-20
    Description: T cell activation is a well-established model for studying cellular responses to exogenous stimulation. Using strand-specific RNA-seq, we observed that intron retention is prevalent in polyadenylated transcripts in resting CD4 + T cells and is significantly reduced upon T cell activation. Several lines of evidence suggest that intron-retained transcripts are less stable than fully spliced transcripts. Strikingly, the decrease in intron retention (IR) levels correlate with the increase in steady-state mRNA levels. Further, the majority of the genes upregulated in activated T cells are accompanied by a significant reduction in IR. Of these 1583 genes, 185 genes are predominantly regulated at the IR level, and highly enriched in the proteasome pathway, which is essential for proper T cell proliferation and cytokine release. These observations were corroborated in both human and mouse CD4 + T cells. Our study revealed a novel post-transcriptional regulatory mechanism that may potentially contribute to coordinated and/or quick cellular responses to extracellular stimuli such as an acute infection.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    BubbleTree: an intuitive visualization to elucidate tumoral aneuploidy and clonality using next generation sequencing data (2016)
    Oxford University Press
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    Publication Date: 2016-03-01
    Description: Tumors are characterized by properties of genetic instability, heterogeneity, and significant oligoclonality. Elucidating this intratumoral heterogeneity is challenging but important. In this study, we propose a framework, BubbleTree, to characterize the tumor clonality using next generation sequencing (NGS) data. BubbleTree simultaneously elucidates the complexity of a tumor biopsy, estimating cancerous cell purity, tumor ploidy, allele-specific copy number, and clonality and represents this in an intuitive graph. We further developed a three-step heuristic method to automate the interpretation of the BubbleTree graph, using a divide-and-conquer strategy. In this study, we demonstrated the performance of BubbleTree with comparisons to similar commonly used tools such as THetA2, ABSOLUTE, AbsCN-seq and ASCAT, using both simulated and patient-derived data. BubbleTree outperformed these tools, particularly in identifying tumor subclonal populations and polyploidy. We further demonstrated BubbleTree's utility in tracking clonality changes from patients’ primary to metastatic tumor and dating somatic single nucleotide and copy number variants along the tumor clonal evolution. Overall, the BubbleTree graph and corresponding model is a powerful approach to provide a comprehensive spectrum of the heterogeneous tumor karyotype in human tumors. BubbleTree is R-based and freely available to the research community ( https://www.bioconductor.org/packages/release/bioc/html/BubbleTree.html ).
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Interferon gamma (IFN-{gamma}) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription (2012)
    Oxford University Press
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    Publication Date: 2012-02-28
    Description: Chronic inflammation impairs metabolic homeostasis and is intimately correlated with the pathogenesis of type 2 diabetes. The pro-inflammatory cytokine IFN- is an integral part of the metabolic inflammation circuit and contributes significantly to metabolic dysfunction. The underlying mechanism, however, remains largely unknown. In the present study, we report that IFN- disrupts the expression of genes key to cellular metabolism and energy expenditure by repressing the expression and activity of SIRT1 at the transcription level. Further analysis reveals that IFN- requires class II transactivator (CIITA) to repress SIRT1 transcription. CIITA, once induced by IFN-, is recruited to the SIRT1 promoter by hypermethylated in cancer 1 (HIC1) and promotes down-regulation of SIRT1 transcription via active deacetylation of core histones surrounding the SIRT1 proximal promoter. Silencing CIITA or HIC1 restores SIRT1 activity and expression of metabolic genes in skeletal muscle cells challenged with IFN-. Therefore, our data delineate an IFN-/HIC1/CIITA axis that contributes to metabolic dysfunction by suppressing SIRT1 transcription in skeletal muscle cells and as such shed new light on the development of novel therapeutic strategies against type 2 diabetes.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation (2016)
    Oxford University Press
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    Publication Date: 2016-09-03
    Description: The modulation of chromatin structure is a key step in transcription regulation in mammalian cells and eventually determines lineage commitment and differentiation. USF1/2, Setd1a and NURF complexes interact to regulate chromatin architecture in erythropoiesis, but the mechanistic basis for this regulation is hitherto unknown. Here we showed that Setd1a and NURF complexes bind to promoters to control chromatin structural alterations and gene activation in a cell context dependent manner. In human primary erythroid cells USF1/2, H3K4me3 and the NURF complex were significantly co-enriched at transcription start sites of erythroid genes, and their binding was associated with promoter/enhancer accessibility that resulted from nucleosome repositioning. Mice deficient for Setd1a , an H3K4 trimethylase, in the erythroid compartment exhibited reduced Ter119/CD71 positive erythroblasts, peripheral blood RBCs and hemoglobin levels. Loss of Setd1a led to a reduction of promoter-associated H3K4 methylation, inhibition of gene transcription and blockade of erythroid differentiation. This was associated with alterations in NURF complex occupancy at erythroid gene promoters and reduced chromatin accessibility. Setd1a deficiency caused decreased associations between enhancer and promoter looped interactions as well as reduced expression of erythroid genes such as the adult β-globin gene. These data indicate that Setd1a and NURF complexes are specifically targeted to and coordinately regulate erythroid promoter chromatin dynamics during erythroid lineage differentiation.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    The structural basis for the oligomerization of the N-terminal domain of SATB1 (2012)
    Oxford University Press
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    Publication Date: 2012-05-13
    Description: Special AT-rich sequence-binding protein 1 (SATB1) is a global chromatin organizer and gene expression regulator essential for T-cell development and breast cancer tumor growth and metastasis. The oligomerization of the N-terminal domain of SATB1 is critical for its biological function. We determined the crystal structure of the N-terminal domain of SATB1. Surprisingly, this domain resembles a ubiquitin domain instead of the previously proposed PDZ domain. Our results also reveal that SATB1 can form a tetramer through its N-terminal domain. The tetramerization of SATB1 plays an essential role in its binding to highly specialized DNA sequences. Furthermore, isothermal titration calorimetry results indicate that the SATB1 tetramer can bind simultaneously to two DNA targets. Based on these results, we propose a molecular model whereby SATB1 regulates the expression of multiple genes both locally and at a distance.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Structural insights into Paf1 complex assembly and histone binding (2013)
    Oxford University Press
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    Publication Date: 2013-12-07
    Description: The highly conserved Paf1 complex (PAF1C) plays critical roles in RNA polymerase II transcription elongation and in the regulation of histone modifications. It has also been implicated in other diverse cellular activities, including posttranscriptional events, embryonic development and cell survival and maintenance of embryonic stem cell identity. Here, we report the structure of the human Paf1/Leo1 subcomplex within PAF1C. The overall structure reveals that the Paf1 and Leo1 subunits form a tightly associated heterodimer through antiparallel beta-sheet interactions. Detailed biochemical experiments indicate that Leo1 binds to PAF1C through Paf1 and that the Ctr9 subunit is the key scaffold protein in assembling PAF1C. Furthermore, we show that the Paf1/Leo1 heterodimer is necessary for its binding to histone H3, the histone octamer, and nucleosome in vitro . Our results shed light on the PAF1C assembly process and substrate recognition during various PAF1C-coordinated histone modifications.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    CANOES: detecting rare copy number variants from whole exome sequencing data (2014)
    Oxford University Press
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    Publication Date: 2014-07-04
    Description: We present CANOES, an algorithm for the detection of rare copy number variants from exome sequencing data. CANOES models read counts using a negative binomial distribution and estimates variance of the read counts using a regression-based approach based on selected reference samples in a given dataset. We test CANOES on a family-based exome sequencing dataset, and show that its sensitivity and specificity is comparable to that of XHMM. Moreover, the method is complementary to Gaussian approximation-based methods (e.g. XHMM or CoNIFER). When CANOES is used in combination with these methods, it will be possible to produce high accuracy calls, as demonstrated by a much reduced and more realistic de novo rate in results from trio data.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    YeastFab: the design and construction of standard biological parts for metabolic engineering in Saccharomyces cerevisiae (2015)
    Oxford University Press
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    Publication Date: 2015-07-25
    Description: It is a routine task in metabolic engineering to introduce multicomponent pathways into a heterologous host for production of metabolites. However, this process sometimes may take weeks to months due to the lack of standardized genetic tools. Here, we present a method for the design and construction of biological parts based on the native genes and regulatory elements in Saccharomyces cerevisiae . We have developed highly efficient protocols (termed YeastFab Assembly) to synthesize these genetic elements as standardized biological parts, which can be used to assemble transcriptional units in a single-tube reaction. In addition, standardized characterization assays are developed using reporter constructs to calibrate the function of promoters. Furthermore, the assembled transcription units can be either assayed individually or applied to construct multi-gene metabolic pathways, which targets a genomic locus or a receiving plasmid effectively, through a simple in vitro reaction. Finally, using β-carotene biosynthesis pathway as an example, we demonstrate that our method allows us not only to construct and test a metabolic pathway in several days, but also to optimize the production through combinatorial assembly of a pathway using hundreds of regulatory biological parts.
    Keywords: Synthetic Biology and Assembly Cloning
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    Global identification of the genetic networks and cis-regulatory elements of the cold response in zebrafish (2015)
    Oxford University Press
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    Publication Date: 2015-10-31
    Description: The transcriptional programs of ectothermic teleosts are directly influenced by water temperature. However, the cis - and trans -factors governing cold responses are not well characterized. We profiled transcriptional changes in eight zebrafish tissues exposed to mildly and severely cold temperatures using RNA-Seq. A total of 1943 differentially expressed genes (DEGs) were identified, from which 34 clusters representing distinct tissue and temperature response expression patterns were derived using the k -means fuzzy clustering algorithm. The promoter regions of the clustered DEGs that demonstrated strong co-regulation were analysed for enriched cis -regulatory elements with a motif discovery program, DREME. Seventeen motifs, ten known and seven novel, were identified, which covered 23% of the DEGs. Two motifs predicted to be the binding sites for the transcription factors Bcl6 and Jun, respectively, were chosen for experimental verification, and they demonstrated the expected cold-induced and cold-repressed patterns of gene regulation. Protein interaction modeling of the network components followed by experimental validation suggested that Jun physically interacts with Bcl6 and might be a hub factor that orchestrates the cold response in zebrafish. Thus, the methodology used and the regulatory networks uncovered in this study provide a foundation for exploring the mechanisms of cold adaptation in teleosts.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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