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author:("Chen, giwen")
1.  Integrative genomic analyses reveal clinically relevant long non-coding RNA in human cancer 
Despite growing appreciations of the importance of long non-coding RNA (lncRNA) in normal physiology and disease, our knowledge of cancer-related lncRNA remains limited. By repurposing microarray probes, we constructed the expression profile of 10,207 lncRNA genes in approximately 1,300 tumors over four different cancer types. Through integrative analysis of the lncRNA expression profiles with clinical outcome and somatic copy number alteration (SCNA), we identified lncRNA that are associated with cancer subtypes and clinical prognosis, and predicted those that are potential drivers of cancer progression. We validated our predictions by experimentally confirming prostate cancer cell growth dependence on two novel lncRNA. Our analysis provided a resource of clinically relevant lncRNA for development of lncRNA biomarkers and identification of lncRNA therapeutic targets. It also demonstrated the power of integrating publically available genomic datasets and clinical information for discovering disease associated lncRNA.
doi:10.1038/nsmb.2591
PMCID: PMC3702647  PMID: 23728290
2.  Time Frame and Justice Motive: Future Perspective Moderates the Adaptive Function of General Belief in a Just World 
PLoS ONE  2013;8(11):e80668.
Background
The human ability to envision the future, that is, to take a future perspective (FP), plays a key role in the justice motive and its function in transcending disadvantages and misfortunes. The present research investigated whether individual (Study 1) and situational (Study 2) differences in FP moderated the association of general belief in a just world (GBJW) with psychological resilience.
Methodology/Principal Findings
We investigated FP, GBJW, and resilience in sample of adolescents (n = 223) and disaster survivors (n = 218) in China. In Study 1, adolescents revealed stronger GBJW than PBJW, and GBJW uniquely predicted resilience in the daily lives of those with high FP (but not those with low FP). In Study 2, natural priming of FP (vs. no FP) facilitated the association of GBJW with resilience after disaster.
Conclusions/Significance
Supporting predictions, participants endorsed GBJW more strongly than PBJW. Further, GBJW interacted with FP in both studies, such that there was an association between GBJW and resilience at high but not low levels of FP. The results corroborate recent findings suggesting that GBJW may be more psychologically adaptive than PBJW among some populations. They also confirm that focusing on the future is an important aspect of the adaptive function of just-world beliefs.
doi:10.1371/journal.pone.0080668
PMCID: PMC3842919  PMID: 24312235
3.  A Comprehensive View of Nuclear Receptor Cancer Cistromes 
Cancer research  2011;71(22):6940-6947.
Nuclear receptors (NRs) comprise a superfamily of ligand-activated transcription factors that play important roles in both physiology and diseases including cancer. The technologies of Chromatin ImmunoPrecipitation followed by array hybridization (ChIP-chip) or massively parallel sequencing (ChIP-seq) has been used to map, at an unprecedented rate, the in vivo genome-wide binding (cistrome) of NRs in both normal and cancer cells. We developed a curated database of 88 NR cistrome datasets and other associated high-throughput datasets, including 121 collaborating factor cistromes, 94 epigenomes and 319 transcriptomes. Through integrative analysis of the curated NR ChIP-chip/seq datasets, we discovered novel factor-specific noncanonical motifs that may have important regulatory roles. We also revealed a common feature of NR pioneering factors to recognize relatively short and AT-rich motifs. Most NRs bind predominantly to introns and distal intergenetic regions, and binding sites closer to transcription start sites (TSSs) were found to be neither stronger nor more evolutionarily conserved. Interestingly, while most NRs appear to be predominantly transcriptional activators, our analysis suggests that the binding of ESR1, RARA and RARG has both activating and repressive effects. Through meta-analysis of different omic data of the same cancer cell line model from multiple studies, we generated consensus cistrome and expression profiles. We further made probabilistic predictions of the NR target genes by integrating cistrome and transcriptome data, and validated the predictions using expression data from tumor samples. The final database, with comprehensive cistrome, epigenome, transcriptome datasets, and downstream analysis results, constitutes a valuable resource for the nuclear receptor and cancer community.
doi:10.1158/0008-5472.CAN-11-2091
PMCID: PMC3610570  PMID: 21940749
4.  Systematic evaluation of factors influencing ChIP-seq fidelity 
Nature methods  2012;9(6):609-614.
We performed a systematic evaluation of how variations in sequencing depth and other parameters influence interpretation of Chromatin immunoprecipitation (ChIP) followed by sequencing (ChIP-seq) experiments. Using Drosophila S2 cells, we generated ChIP-seq datasets for a site-specific transcription factor (Suppressor of Hairy-wing) and a histone modification (H3K36me3). We detected a chromatin state bias, open chromatin regions yielded higher coverage, which led to false positives if not corrected and had a greater effect on detection specificity than any base-composition bias. Paired-end sequencing revealed that single-end data underestimated ChIP library complexity at high coverage. The removal of reads originating at the same base reduced false-positives while having little effect on detection sensitivity. Even at a depth of ~1 read/bp coverage of mappable genome, ~1% of the narrow peaks detected on a tiling array were missed by ChIP-seq. Evaluation of widely-used ChIP-seq analysis tools suggests that adjustments or algorithm improvements are required to handle datasets with deep coverage.
doi:10.1038/nmeth.1985
PMCID: PMC3477507  PMID: 22522655
5.  Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer 
Cancer cell  2011;20(1):119-131.
Summary
Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25-30% of cases that are ER negative (ER−). Androgen receptor (AR) is expressed in 60-70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER−breast tumors that over-express HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER−/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER−/HER2+ breast cancers.
doi:10.1016/j.ccr.2011.05.026
PMCID: PMC3180861  PMID: 21741601
6.  Cistrome: an integrative platform for transcriptional regulation studies 
Genome Biology  2011;12(8):R83.
The increasing volume of ChIP-chip and ChIP-seq data being generated creates a challenge for standard, integrative and reproducible bioinformatics data analysis platforms. We developed a web-based application called Cistrome, based on the Galaxy open source framework. In addition to the standard Galaxy functions, Cistrome has 29 ChIP-chip- and ChIP-seq-specific tools in three major categories, from preliminary peak calling and correlation analyses to downstream genome feature association, gene expression analyses, and motif discovery. Cistrome is available at http://cistrome.org/ap/.
doi:10.1186/gb-2011-12-8-r83
PMCID: PMC3245621  PMID: 21859476
7.  Estimation of affinities of ligands in mixtures via magnetic recovery of target-ligand complexes and chromatographic analyses: chemometrics and an experimental model 
BMC Biotechnology  2011;11:44.
Abstract
Background
The combinatorial library strategy of using multiple candidate ligands in mixtures as library members is ideal in terms of cost and efficiency, but needs special screening methods to estimate the affinities of candidate ligands in such mixtures. Herein, a new method to screen candidate ligands present in unknown molar quantities in mixtures was investigated.
Results
The proposed method involves preparing a processed-mixture-for-screening (PMFS) with each mixture sample and an exogenous reference ligand, initiating competitive binding among ligands from the PMFS to a target immobilized on magnetic particles, recovering target-ligand complexes in equilibrium by magnetic force, extracting and concentrating bound ligands, and analyzing ligands in the PMFS and the concentrated extract by chromatography. The relative affinity of each candidate ligand to its reference ligand is estimated via an approximation equation assuming (a) the candidate ligand and its reference ligand bind to the same site(s) on the target, (b) their chromatographic peak areas are over five times their intercepts of linear response but within their linear ranges, (c) their binding ratios are below 10%. These prerequisites are met by optimizing primarily the quantity of the target used and the PMFS composition ratio.
The new method was tested using the competitive binding of biotin derivatives from mixtures to streptavidin immobilized on magnetic particles as a model. Each mixture sample containing a limited number of candidate biotin derivatives with moderate differences in their molar quantities were prepared via parallel-combinatorial-synthesis (PCS) without purification, or via the pooling of individual compounds. Some purified biotin derivatives were used as reference ligands. This method showed resistance to variations in chromatographic quantification sensitivity and concentration ratios; optimized conditions to validate the approximation equation could be applied to different mixture samples. Relative affinities of candidate biotin derivatives with unknown molar quantities in each mixture sample were consistent with those estimated by a homogenous method using their purified counterparts as samples.
Conclusions
This new method is robust and effective for each mixture possessing a limited number of candidate ligands whose molar quantities have moderate differences, and its integration with PCS has promise to routinely practice the mixture-based library strategy.
doi:10.1186/1472-6750-11-44
PMCID: PMC3096923  PMID: 21545719
8.  MM-ChIP enables integrative analysis of cross-platform and between-laboratory ChIP-chip or ChIP-seq data 
Genome Biology  2011;12(2):R11.
The ChIP-chip and ChIP-seq techniques enable genome-wide mapping of in vivo protein-DNA interactions and chromatin states. The cross-platform and between-laboratory variation poses a challenge to the comparison and integration of results from different ChIP experiments. We describe a novel method, MM-ChIP, which integrates information from cross-platform and between-laboratory ChIP-chip or ChIP-seq datasets. It improves both the sensitivity and the specificity of detecting ChIP-enriched regions, and is a useful meta-analysis tool for driving discoveries from multiple data sources.
doi:10.1186/gb-2011-12-2-r11
PMCID: PMC3188793  PMID: 21284836
9.  Quantitative Comparative Analysis of the Bio-Active and Toxic Constituents of Leaves and Spikes of Schizonepeta tenuifolia at Different Harvesting Times 
A GC-MS-Selected Ion Monitoring (SIM) detection method was developed for simultaneous determination of four monoterpenes: (−)-menthone, (+)-pulegone, (−)-limonene and (+)-menthofuran as the main bio-active and toxic constituents, and four other main compounds in the volatile oils of Schizonepeta tenuifolia (ST) leaves and spikes at different harvesting times. The results showed that the method was simple, sensitive and reproducible, and that harvesting time was a possible key factor in influencing the quality of ST leaves, but not its spikes. The research might be helpful for determining the harvesting time of ST samples and establishing a validated method for the quality control of ST volatile oil and other relative products.
doi:10.3390/ijms12106635
PMCID: PMC3210999  PMID: 22072908
Schizonepeta tenuifolia; menthone; pulegone; limonene; menthofuran; harvesting time
10.  Natural Selection against Protein Aggregation on Self-Interacting and Essential Proteins in Yeast, Fly, and Worm 
Molecular Biology and Evolution  2008;25(8):1530-1533.
Protein aggregation is the phenomenon of protein self-association potentially leading to detrimental effects on physiology, which is closely related to numerous human diseases such as Alzheimer's and Parkinson's disease. Despite progress in understanding the mechanism of protein aggregation, how natural selection against protein aggregation acts on subunits of protein complexes and on proteins with different contributions to organism fitness remains largely unknown. Here, we perform a proteome-wide analysis by using an experimentally validated algorithm TANGO and utilizing sequence, interactomic and phenotype-based functional genomic data from yeast, fly, and nematode. We find that proteins that are capable of forming homooligomeric complex have lower aggregation propensity compared with proteins that do not function as homooligomer. Further, proteins that are essential to the fitness of an organism have lower aggregation propensity compared with nonessential ones. Our finding suggests that the selection force against protein aggregation acts across different hierarchies of biological system.
doi:10.1093/molbev/msn122
PMCID: PMC2727382  PMID: 18503047
natural selection; protein aggregation; functional genomics; proteome; Drosophila melanogaster; Caenorhabditis elegans
11.  Protein Folding: Then and Now 
Over the past three decades the protein folding field has undergone monumental changes. Originally a purely academic question, how a protein folds has now become vital in understanding diseases and our abilities to rationally manipulate cellular life by engineering protein folding pathways. We review and contrast past and recent developments in the protein folding field. Specifically, we discuss the progress in our understanding of protein folding thermodynamics and kinetics, the properties of evasive intermediates, and unfolded states. We also discuss how some abnormalities in protein folding lead to protein aggregation and human diseases.
doi:10.1016/j.abb.2007.05.014
PMCID: PMC2173875  PMID: 17585870

Results 1-11 (11)