Sunday, November 4, 2012
Thursday, May 5, 2011
NOA: a novel Network Ontology Analysis method
NOA: a novel Network Ontology Analysis method
Jiguang Wang1, Qiang Huang1, Zhi-Ping Liu2, Yong Wang1, Ling-Yun Wu1, Luonan Chen2,3,* and Xiang-Sun Zhang1,*
+ Author Affiliations
1Key Laboratory of Management, Decision and Information Systems, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, 2Key Laboratory of Systems Biology, SIBS-Novo Nordisk Translational Research Centre for PreDiabetes, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200233, China and 3Collaborative Research Center for Innovative Mathematical Modelling, Institute of Industrial Science, University of Tokyo, Tokyo 153-8505, Japan
*To whom correspondence should be addressed. Tel: +86-21-6436-5937; Fax: +86-21-5497-2551; Email: lnchen@sibs.ac.cn
Correspondence may also be addressed to Xiang-Sun Zhang. Tel: +86-10-6256-1440; Fax: +86-10-6256-1963; Email: zxs@amt.ac.cn
Received December 13, 2010.
Revision received April 3, 2011.
Accepted April 5, 2011.
Abstract
Gene ontology analysis has become a popular and important tool in bioinformatics study, and current ontology analyses are mainly conducted in individual gene or a gene list. However, recent molecular network analysis reveals that the same list of genes with different interactions may perform different functions. Therefore, it is necessary to consider molecular interactions to correctly and specifically annotate biological networks. Here, we propose a novel Network Ontology Analysis (NOA) method to perform gene ontology enrichment analysis on biological networks. Specifically, NOA first defines link ontology that assigns functions to interactions based on the known annotations of joint genes via optimizing two novel indexes ‘Coverage’ and ‘Diversity’. Then, NOA generates two alternative reference sets to statistically rank the enriched functional terms for a given biological network. We compare NOA with traditional enrichment analysis methods in several biological networks, and find that: (i) NOA can capture the change of functions not only in dynamic transcription regulatory networks but also in rewiring protein interaction networks while the traditional methods cannot and (ii) NOA can find more relevant and specific functions than traditional methods in different types of static networks. Furthermore, a freely accessible web server for NOA has been developed at http://www.aporc.org/noa/.
Jiguang Wang1, Qiang Huang1, Zhi-Ping Liu2, Yong Wang1, Ling-Yun Wu1, Luonan Chen2,3,* and Xiang-Sun Zhang1,*
+ Author Affiliations
1Key Laboratory of Management, Decision and Information Systems, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, 2Key Laboratory of Systems Biology, SIBS-Novo Nordisk Translational Research Centre for PreDiabetes, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200233, China and 3Collaborative Research Center for Innovative Mathematical Modelling, Institute of Industrial Science, University of Tokyo, Tokyo 153-8505, Japan
*To whom correspondence should be addressed. Tel: +86-21-6436-5937; Fax: +86-21-5497-2551; Email: lnchen@sibs.ac.cn
Correspondence may also be addressed to Xiang-Sun Zhang. Tel: +86-10-6256-1440; Fax: +86-10-6256-1963; Email: zxs@amt.ac.cn
Received December 13, 2010.
Revision received April 3, 2011.
Accepted April 5, 2011.
Abstract
Gene ontology analysis has become a popular and important tool in bioinformatics study, and current ontology analyses are mainly conducted in individual gene or a gene list. However, recent molecular network analysis reveals that the same list of genes with different interactions may perform different functions. Therefore, it is necessary to consider molecular interactions to correctly and specifically annotate biological networks. Here, we propose a novel Network Ontology Analysis (NOA) method to perform gene ontology enrichment analysis on biological networks. Specifically, NOA first defines link ontology that assigns functions to interactions based on the known annotations of joint genes via optimizing two novel indexes ‘Coverage’ and ‘Diversity’. Then, NOA generates two alternative reference sets to statistically rank the enriched functional terms for a given biological network. We compare NOA with traditional enrichment analysis methods in several biological networks, and find that: (i) NOA can capture the change of functions not only in dynamic transcription regulatory networks but also in rewiring protein interaction networks while the traditional methods cannot and (ii) NOA can find more relevant and specific functions than traditional methods in different types of static networks. Furthermore, a freely accessible web server for NOA has been developed at http://www.aporc.org/noa/.
Tuesday, May 3, 2011
Differential genome-wide profiling of tandem 3′ UTRs among human breast cancer and normal cells by high-throughput sequencing
Differential genome-wide profiling of tandem 3′ UTRs among human breast cancer and normal cells by high-throughput sequencing
Yonggui Fu1, Yu Sun1, Yuxin Li1, Jie Li, Xingqiang Rao, Chong Chen and Anlong Xu2
+ Author Affiliations
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, College of Life Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou, 510006, P.R. China
↵1 These authors contributed equally to this work.
Abstract
Tandem 3′ UTRs produced by alternative polyadenylation (APA) play an important role in gene expression by impacting mRNA stability, translation, and translocation in cells. Several studies have investigated APA site switching in various physiological states; nevertheless, they only focused on either the genes with two known APA sites or several candidate genes. Here, we developed a strategy to study APA sites in a genome-wide fashion with second-generation sequencing technology which could not only identify new polyadenylation sites but also analyze the APA site switching of all genes, especially those with more than two APA sites. We used this strategy to explore the profiling of APA sites in two human breast cancer cell lines, MCF7 and MB231, and one cultured mammary epithelial cell line, MCF10A. More than half of the identified polyadenylation sites are not included in human poly(A) databases. While MCF7 showed shortening 3′ UTRs, more genes in MB231 switched to distal poly(A) sites. Several gene ontology (GO) terms and pathways were enriched in the list of genes with switched APA sites, including cell cycle, apoptosis, and metabolism. These results suggest a more complex regulation of APA sites in cancer cells than previously thought. In short, our novel unbiased method can be a powerful approach to cost-effectively investigate the complex mechanism of 3′ UTR switching in a genome-wide fashion among various physiological processes and diseases.
Yonggui Fu1, Yu Sun1, Yuxin Li1, Jie Li, Xingqiang Rao, Chong Chen and Anlong Xu2
+ Author Affiliations
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, College of Life Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou, 510006, P.R. China
↵1 These authors contributed equally to this work.
Abstract
Tandem 3′ UTRs produced by alternative polyadenylation (APA) play an important role in gene expression by impacting mRNA stability, translation, and translocation in cells. Several studies have investigated APA site switching in various physiological states; nevertheless, they only focused on either the genes with two known APA sites or several candidate genes. Here, we developed a strategy to study APA sites in a genome-wide fashion with second-generation sequencing technology which could not only identify new polyadenylation sites but also analyze the APA site switching of all genes, especially those with more than two APA sites. We used this strategy to explore the profiling of APA sites in two human breast cancer cell lines, MCF7 and MB231, and one cultured mammary epithelial cell line, MCF10A. More than half of the identified polyadenylation sites are not included in human poly(A) databases. While MCF7 showed shortening 3′ UTRs, more genes in MB231 switched to distal poly(A) sites. Several gene ontology (GO) terms and pathways were enriched in the list of genes with switched APA sites, including cell cycle, apoptosis, and metabolism. These results suggest a more complex regulation of APA sites in cancer cells than previously thought. In short, our novel unbiased method can be a powerful approach to cost-effectively investigate the complex mechanism of 3′ UTR switching in a genome-wide fashion among various physiological processes and diseases.
Sunday, April 24, 2011
Epigenetic Regulation of Cell Type–Specific Expression Patterns in the Human Mammary Epithelium
Epigenetic Regulation of Cell Type–Specific Expression Patterns in the Human Mammary Epithelium
Differentiation is an epigenetic program that involves the gradual loss of pluripotency and acquisition of cell type–specific features. Understanding these processes requires genome-wide analysis of epigenetic and gene expression profiles, which have been challenging in primary tissue samples due to limited numbers of cells available. Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, as well as gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type–specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation.
Differentiation is an epigenetic program that involves the gradual loss of pluripotency and acquisition of cell type–specific features. Understanding these processes requires genome-wide analysis of epigenetic and gene expression profiles, which have been challenging in primary tissue samples due to limited numbers of cells available. Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, as well as gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type–specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation.
Thursday, April 21, 2011
Extensive chromatin remodelling and establishment of transcription factor ‘hotspots’ during early adipogenesis
The EMBO Journal (2011) 30, 1459 - 1472 doi:10.1038/emboj.2011.65
Published online: 22 March 2011
Subject Category: Chromatin and Transcription
Extensive chromatin remodelling and establishment of transcription factor ‘hotspots’ during early adipogenesis
Rasmus Siersbæk1, Ronni Nielsen1, Sam John2, Myong-Hee Sung2, Songjoon Baek2, Anne Loft1, Gordon L Hager2 and Susanne Mandrup1
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Correspondence to:
Susanne Mandrup, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, Odense 5230, Denmark. Tel.: +45 6550 2340; Fax: +45 6550 2467; E-mail: s.mandrup@bmb.sdu.dk
Gordon L Hager, Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-5055, USA. Tel.: +1 301 496 9867; Fax: +1 301 496 4951; E-mail: hagerg@dce41.nci.nih.gov
Received 30 September 2010; Accepted 17 February 2011
Adipogenesis is tightly controlled by a complex network of transcription factors acting at different stages of differentiation. Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein (C/EBP) family members are key regulators of this process. We have employed DNase I hypersensitive site analysis to investigate the genome-wide changes in chromatin structure that accompany the binding of adipogenic transcription factors. These analyses revealed a dramatic and dynamic modulation of the chromatin landscape during the first hours of adipocyte differentiation that coincides with cooperative binding of multiple early transcription factors (including glucocorticoid receptor, retinoid X receptor, Stat5a, C/EBPβ and -δ) to transcription factor ‘hotspots’. Our results demonstrate that C/EBPβ marks a large number of these transcription factor ‘hotspots’ before induction of differentiation and chromatin remodelling and is required for their establishment. Furthermore, a subset of early remodelled C/EBP-binding sites persists throughout differentiation and is later occupied by PPARγ, indicating that early C/EBP family members, in addition to their well-established role in activation of PPARγ transcription, may act as pioneering factors for PPARγ binding.
Published online: 22 March 2011
Subject Category: Chromatin and Transcription
Extensive chromatin remodelling and establishment of transcription factor ‘hotspots’ during early adipogenesis
Rasmus Siersbæk1, Ronni Nielsen1, Sam John2, Myong-Hee Sung2, Songjoon Baek2, Anne Loft1, Gordon L Hager2 and Susanne Mandrup1
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Correspondence to:
Susanne Mandrup, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, Odense 5230, Denmark. Tel.: +45 6550 2340; Fax: +45 6550 2467; E-mail: s.mandrup@bmb.sdu.dk
Gordon L Hager, Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-5055, USA. Tel.: +1 301 496 9867; Fax: +1 301 496 4951; E-mail: hagerg@dce41.nci.nih.gov
Received 30 September 2010; Accepted 17 February 2011
Adipogenesis is tightly controlled by a complex network of transcription factors acting at different stages of differentiation. Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein (C/EBP) family members are key regulators of this process. We have employed DNase I hypersensitive site analysis to investigate the genome-wide changes in chromatin structure that accompany the binding of adipogenic transcription factors. These analyses revealed a dramatic and dynamic modulation of the chromatin landscape during the first hours of adipocyte differentiation that coincides with cooperative binding of multiple early transcription factors (including glucocorticoid receptor, retinoid X receptor, Stat5a, C/EBPβ and -δ) to transcription factor ‘hotspots’. Our results demonstrate that C/EBPβ marks a large number of these transcription factor ‘hotspots’ before induction of differentiation and chromatin remodelling and is required for their establishment. Furthermore, a subset of early remodelled C/EBP-binding sites persists throughout differentiation and is later occupied by PPARγ, indicating that early C/EBP family members, in addition to their well-established role in activation of PPARγ transcription, may act as pioneering factors for PPARγ binding.
The 2011 Pulitzer Prize Winners
For a distinguished example of explanatory reporting that illuminates a significant and complex subject, demonstrating mastery of the subject, lucid writing and clear presentation, using any available journalistic tool including text reporting, videos, databases, multimedia or interactive presentations or any combination of those formats, in print or online or both, Ten thousand dollars ($10,000).
Awarded Mark Johnson, Kathleen Gallagher, Gary Porter, Lou Saldivar and Alison Sherwood of the Milwaukee Journal Sentinel for their lucid examination of an epic effort to use genetic technology to save a 4-year-old boy imperiled by a mysterious disease, told with words, graphics, videos and other images
Finalists
Also nominated as finalists in this category were: The Wall Street Journal Staff for its penetration of the shadowy world of fraud and abuse in Medicare, probing previously concealed government databases to identify millions of dollars in waste and corrupt practices; and The Washington Post Staff for its exploration of how the military is using trauma surgery, brain science and other techniques both old and new to reduce fatalities among the wounded in warfare, telling the story with words, images and other tools.
Awarded Mark Johnson, Kathleen Gallagher, Gary Porter, Lou Saldivar and Alison Sherwood of the Milwaukee Journal Sentinel for their lucid examination of an epic effort to use genetic technology to save a 4-year-old boy imperiled by a mysterious disease, told with words, graphics, videos and other images
Finalists
Also nominated as finalists in this category were: The Wall Street Journal Staff for its penetration of the shadowy world of fraud and abuse in Medicare, probing previously concealed government databases to identify millions of dollars in waste and corrupt practices; and The Washington Post Staff for its exploration of how the military is using trauma surgery, brain science and other techniques both old and new to reduce fatalities among the wounded in warfare, telling the story with words, images and other tools.
Wednesday, April 20, 2011
A User's Guide to the Encyclopedia of DNA Elements (ENCODE)
Abstract Top
The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.
The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.
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