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  • 1
    Keywords: APOPTOSIS ; GENES ; GENOME ; DOWN-REGULATION ; LYMPHOMA ; TARGETS ; METHYLATION ; HUMAN CANCER-CELLS ; epigenetic regulation ; SIGNATURES
    Abstract: Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of hematopoietic malignancies, including chronic lymphocytic leukemia (CLL). However, an understanding of the mechanisms that cause aberrant miRNA transcriptional control is lacking. In this study, we comprehensively investigated the role and extent of miRNA epigenetic regulation in CLL. Genome-wide profiling conducted on 24 CLL and 10 healthy B cell samples revealed global DNA methylation patterns upstream of miRNA sequences that distinguished malignant from healthy cells and identified putative miRNA promoters. Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation. DNA hypomethylation accounted for more than 60% of all aberrant promoter-associated DNA methylation in CLL, and promoter DNA hypomethylation was restricted to well-defined regions. Individual hyper- and hypomethylated promoters allowed discrimination of CLL samples from healthy controls. Promoter DNA methylation patterns were confirmed in an independent patient cohort, with 11 miRNAs consistently showing an inverse correlation between DNA methylation status and expression level. Together, our findings characterize the role of epigenetic changes in the regulation of miRNA transcription and create a repository of disease-specific promoter regions that may provide additional insights into the pathogenesis of CLL. Cancer Res; 72(15); 3775-85. (c)2012 AACR.
    Type of Publication: Journal article published
    PubMed ID: 22710432
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  • 2
    Keywords: LUNG-CANCER ; DISEASE ; RISK ; GENES ; GENOME ; SEQUENCE ; MASS-SPECTROMETRY ; NICOTINIC ACETYLCHOLINE-RECEPTORS ; CANCER SUSCEPTIBILITY LOCUS ; 15Q25.1
    Abstract: Genome-wide association studies have highlighted three major lung cancer susceptibility regions at 15q25.1, 5p15.33 and 6p21.33. To gain insight into the possible mechanistic relevance of the genes in these regions, we investigated the regulation of candidate susceptibility gene expression by epigenetic alterations in healthy and lung tumor tissues. For genes up or downregulated in lung tumors, the influence of genetic variants on DNA methylation was investigated and in vitro studies were performed. We analyzed 394 CpG units within 19 CpG islands in the susceptibility regions in a screening set of 34 patients. Significant findings were validated in an independent patient set (n=50) with available DNA and RNA. The most consistent overall DNA methylation difference between tumor and adjacent normal tissue on 15q25 was tumor hypomethylation in the promoter region of CHRNB4 with a median difference of 8% (P〈0.001), which resulted in overexpression of the transcript in tumors (P〈0.001). Confirming previous studies, we also found hypermethylation in CHRNA3 and telomerase reverse transcriptase (TERT) with significant expression changes. Decitabine treatment of H1299 cells resulted in reduced methylation levels in gene promoters, elevated transcript levels of CHRNB4 and CHRNA3, and a slight downregulation of TERT demonstrating epigenetic regulation of lung cancer cells. Single-nucleotide polymorphisms rs421629 on 5p15.33 and rs1948, rs660652, rs8040868 and rs2036527 on 15q25.1, previously identified as lung cancer risk or nicotine-addiction modifiers, were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4 (P〈0.001), respectively, in two independent sample sets (n=82; n=150). In addition, CHRNB4 knockdown in two different cell lines (A549 and H1299) resulted in reduced proliferation (P(A549)〈0.05;P(H1299)〈0.001) and propensity to form colonies in H1299 cells. These results suggest epigenetic deregulation of nicotinic acetylcholine receptor subunit (nAChR) genes which in the case of CHRNB4 is strongly associated with genetic lung cancer susceptibility variants and a functional impact on tumorigenic potential.Oncogene advance online publication, 3 September 2012; doi:10.1038/onc.2012.344.
    Type of Publication: Journal article published
    PubMed ID: 22945651
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  • 3
    Keywords: REDUCTION ; PATTERNS ; DATABASE ; SECONDARY STRUCTURE ; OXIDATION ; AMINO-ACID-COMPOSITION ; INTRINSICALLY UNSTRUCTURED PROTEINS ; CONNECTIVITY ; WEB SERVER ; CYSTEINES
    Abstract: Protein disulfide bond is formed during post-translational modifications, and has been implicated in various physiological and pathological processes. Proper localization of disulfide bonds also facilitates the prediction of protein three-dimensional (3D) structure. However, it is both time-consuming and labor-intensive using conventional experimental approaches to determine disulfide bonds, especially for large-scale data sets. Since there are also some limitations for disulfide bond prediction based on 3D structure features, developing sequence-based, convenient and fast-speed computational methods for both inter- and intra-chain disulfide bond prediction is necessary. In this study, we developed a computational method for both types of disulfide bond prediction based on maximum relevance and minimum redundancy (mRMR) method followed by incremental feature selection (IFS), with nearest neighbor algorithm as its prediction model. Features of sequence conservation, residual disorder, and amino acid factor are used for inter-chain disulfide bond prediction. And in addition to these features, sequential distance between a pair of cysteines is also used for intra-chain disulfide bond prediction. Our approach achieves a prediction accuracy of 0.8702 for inter-chain disulfide bond prediction using 128 features and 0.9219 for intra-chain disulfide bond prediction using 261 features. Analysis of optimal feature set indicated key features and key sites for the disulfide bond formation. Interestingly, comparison of top features between interand intra-chain disulfide bonds revealed the similarities and differences of the mechanisms of forming these two types of disulfide bonds, which might help understand more of the mechanisms and provide clues to further experimental studies in this research field.
    Type of Publication: Journal article published
    PubMed ID: 22591475
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  • 4
    Keywords: PROTEINS ; SUBCELLULAR-LOCALIZATION ; drug design ; SIGNAL PEPTIDES ; RATE LAWS ; FUNCTIONAL-GROUP COMPOSITION ; PROTEASE CLEAVAGE SITES ; STATE ENZYME-KINETICS ; BINDING MECHANISM ; GRAPHIC RULES
    Abstract: Knowledge of mechanism of small molecules in metabolic pathway is critical to design specific and effective inhibitors for metabolic pathway. As some small molecules are involved in more than one pathway, it is crucial to use an accurate and robust approach to correctly map the small molecule in specific metabolic pathway that it is involved in. In this article, small molecules are studied using the Minimal-Redundancy-Maximal-Relevance-Forward Feature Search (mRMR-FFS) method combined with Multi-task learning method based on K-nearest neighbor (KNN) Algorithms method. Forty-five important chemical features were found based on 10-folds cross validation test from original data set containing 61 features. By applying KNN method with these forty-five selected features, the accuracy rate of prediction model could achieve 68.2% for the 10-folds cross validation test. It is promosing that our two stage scheme can be a useful approach for searching new effective competitive drugs in metabolic pathway.
    Type of Publication: Journal article published
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  • 5
    Keywords: CANCER ; PATHWAY ; GENE-EXPRESSION ; TRANSCRIPTION FACTOR ; PROGRESSION ; chemotherapy ; EMBRYONIC STEM-CELLS ; PROMOTER HYPERMETHYLATION ; AML ; TUMOR-NECROSIS
    Abstract: BACKGROUND: Aberrant DNA methylation is frequently found in human malignancies including acute myeloid leukemia (AML). While most studies focus on later disease stages, the onset of aberrant DNA methylation events and their dynamics during leukemic progression are largely unknown. METHODS: We screened genome-wide for aberrant CpG island methylation in three disease stages of a murine AML model that is driven by hypomorphic expression of the hematopoietic transcription factor PU.1. DNA methylation levels of selected genes were correlated with methylation levels of CD34+ cells and lineage negative, CD127-, c-Kit+, Sca-1+ cells; common myeloid progenitors; granulocyte-macrophage progenitors; and megakaryocyte-erythroid progenitors. RESULTS: We identified 1,184 hypermethylated array probes covering 762 associated genes in the preleukemic stage. During disease progression, the number of hypermethylated genes increased to 5,465 in the late leukemic disease stage. Using publicly available data, we found a significant enrichment of PU.1 binding sites in the preleukemic hypermethylated genes, suggesting that shortage of PU.1 makes PU.1 binding sites in the DNA accessible for aberrant methylation. Many known AML associated genes such as RUNX1 and HIC1 were found among the preleukemic hypermethylated genes. Nine novel hypermethylated genes, FZD5, FZD8, PRDM16, ROBO3, CXCL14, BCOR, ITPKA, HES6 and TAL1, the latter four being potential PU.1 targets, were confirmed to be hypermethylated in human normal karyotype AML patients, underscoring the relevance of the mouse model for human AML. CONCLUSIONS: Our study identified early aberrantly methylated genes as potential contributors to onset and progression of AML.
    Type of Publication: Journal article published
    PubMed ID: 24944583
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  • 6
    Keywords: IN-VIVO ; GENOME ; DIFFERENTIATION ; HEMATOPOIETIC STEM-CELLS ; ACUTE MYELOID-LEUKEMIA ; Hox genes ; SELF-RENEWAL ; QUIESCENCE ; LINEAGE COMMITMENT ; LONG NONCODING RNAS
    Abstract: In this study, we present integrated quantitative proteome, transcriptome, and methylome analyses of hematopoietic stem cells (HSCs) and four multipotent progenitor (MPP) populations. From the characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps. DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methylation correlates inversely with gene expression at key loci. Our data reveal the differential expression landscape of 493 transcription factors and 682 lncRNAs and highlight specific expression clusters operating in HSCs. We also found an unexpectedly dynamic pattern of transcript isoform regulation, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells. This study provides a comprehensive genome-wide resource for the functional exploration of molecular, cellular, and epigenetic regulation at the top of the hematopoietic hierarchy.
    Type of Publication: Journal article published
    PubMed ID: 25158935
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  • 7
    Keywords: genomics ; PACKAGE ; CIRCOS
    Abstract: SUMMARY: Circular layout is an efficient way for the visualization of huge amounts of genomic information. Here we present the circlize package, which provides an implementation of circular layout generation in R as well as an enhancement of available software. The flexibility of this package is based on the usage of low-level graphics functions such that self-defined high-level graphics can be easily implemented by users for specific purposes. Together with the seamless connection between the powerful computational and visual environment in R, circlize gives users more convenience and freedom to design figures for better understanding genomic patterns behind multi-dimensional data. AVAILABILITY AND IMPLEMENTATION: circlize is available at the Comprehensive R Archive Network (CRAN): http://cran.r-project.org/web/packages/circlize/
    Type of Publication: Journal article published
    PubMed ID: 24930139
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  • 8
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; PATHWAY ; NETWORK ; PROTEIN ; IDENTIFICATION ; DATABASE ; HEPATITIS-B
    Abstract: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide and mostly occurs in viral hepatitis endemic areas such as China. Knowledge of HCC-related genes may lead to an early detection of HCC and develop molecularly targeted therapeutics, reducing mortality and improving a patient's prognosis significantly. Therefore, it is valuable and important for us to identify common characters of HCC related genes. In this study, we proposed a computational method to predict HCC related genes based on Gene Ontology terms and KEGG terms using Random Forest (RF), in which features were optimized by maximum relevance minimum redundancy (mRMR) and incremental feature selection (IFS). 224 HCC gene candidates were compiled from some databases, while 11,200non-HCC gene candidates were randomly selected from Ensemble database. 10 candidate datasets were constructed by dividing non-HCC gene candidates into 10 groups. Each gene in datasets was encoded by 13,126 features including 12,887 Gene Ontology enrichment scores and 239 KEGG enrichment scores. Finally, an optimal feature set including 615 GO terms and 11 KEGG pathways was discovered. Through analysis, we found these features were closely related to HCC, which means our method is effective for discovering HCC related genes, and it is hopeful that it can also be used to predict and analyze genes for other types of cancer.
    Type of Publication: Journal article published
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  • 9
    Keywords: CANCER ; METABOLISM ; fibroblasts ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; MUTATIONS ; PURIFICATION ; CHILDREN ; ENZYME ; PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY ; NOVO NUCLEOTIDE BIOSYNTHESIS
    Abstract: Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL.
    Type of Publication: Journal article published
    PubMed ID: 25962120
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  • 10
    Abstract: Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.
    Type of Publication: Journal article published
    PubMed ID: 26780610
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