Dataset Information

Characterizing genes with distinct methylation patterns in the context of protein-protein interaction network: application to human brain tissues.

ABSTRACT:

Background

DNA methylation is an essential epigenetic mechanism involved in transcriptional control. However, how genes with different methylation patterns are assembled in the protein-protein interaction network (PPIN) remains a mystery.

Results

In the present study, we systematically dissected the characterization of genes with different methylation patterns in the PPIN. A negative association was detected between the methylation levels in the brain tissues and topological centralities. By focusing on two classes of genes with considerably different methylation levels in the brain tissues, namely the low methylated genes (LMGs) and high methylated genes (HMGs), we found that their organizing principles in the PPIN are distinct. The LMGs tend to be the center of the PPIN, and attacking them causes a more deleterious effect on the network integrity. Furthermore, the LMGs express their functions in a modular pattern and substantial differences in functions are observed between the two types of genes. The LMGs are enriched in the basic biological functions, such as binding activity and regulation of transcription. More importantly, cancer genes, especially recessive cancer genes, essential genes, and aging-related genes were all found more often in the LMGs. Additionally, our analysis presented that the intra-classes communications are enhanced, but inter-classes communications are repressed. Finally, a functional complementation was revealed between methylation and miRNA regulation in the human genome.

Conclusions

We have elucidated the assembling principles of genes with different methylation levels in the context of the PPIN, providing key insights into the complex epigenetic regulation mechanisms.

SUBMITTER: Li Y

PROVIDER: S-EPMC3680465 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Characterizing genes with distinct methylation patterns in the context of protein-protein interaction network: application to human brain tissues.

Li Yongsheng Y Xu Juan J Chen Hong H Zhao Zheng Z Li Shengli S Bai Jing J Wu Aiwei A Jiang Chunjie C Wang Yuan Y Su Bin B Li Xia X

PloS one 20130612 6

<h4>Background</h4>DNA methylation is an essential epigenetic mechanism involved in transcriptional control. However, how genes with different methylation patterns are assembled in the protein-protein interaction network (PPIN) remains a mystery.<h4>Results</h4>In the present study, we systematically dissected the characterization of genes with different methylation patterns in the PPIN. A negative association was detected between the methylation levels in the brain tissues and topological centr ...[more]

PMID: 23776563

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Project description:Interactions of proteins regulate signaling, catalysis, gene expression and many other cellular functions. Therefore, characterizing the entire human interactome is a key effort in current proteomics research. This challenge is complicated by the dynamic nature of protein-protein interactions (PPIs), which are conditional on the cellular context: both interacting proteins must be expressed in the same cell and localized in the same organelle to meet. Additionally, interactions underlie a delicate control of signaling pathways, e.g. by post-translational modifications of the protein partners - hence, many diseases are caused by the perturbation of these mechanisms. Despite the high degree of cell-state specificity of PPIs, many interactions are measured under artificial conditions (e.g. yeast cells are transfected with human genes in yeast two-hybrid assays) or even if detected in a physiological context, this information is missing from the common PPI databases. To overcome these problems, we developed a method that assigns context information to PPIs inferred from various attributes of the interacting proteins: gene expression, functional and disease annotations, and inferred pathways. We demonstrate that context consistency correlates with the experimental reliability of PPIs, which allows us to generate high-confidence tissue- and function-specific subnetworks. We illustrate how these context-filtered networks are enriched in bona fide pathways and disease proteins to prove the ability of context-filters to highlight meaningful interactions with respect to various biological questions. We use this approach to study the lung-specific pathways used by the influenza virus, pointing to IRAK1, BHLHE40 and TOLLIP as potential regulators of influenza virus pathogenicity, and to study the signalling pathways that play a role in Alzheimer's disease, identifying a pathway involving the altered phosphorylation of the Tau protein. Finally, we provide the annotated human PPI network via a web frontend that allows the construction of context-specific networks in several ways.

Project description:BackgroundDNA methylation is an epigenetic event that may regulate gene expression. Because of this regulation role, aberrant DNA methylation is often associated with many diseases. Within-sample DNA co-methylation is the similarity of methylation in nearby cytosine sites of a chromosome. It is important to study co-methylation patterns. However, it is not well studied yet, and it is unclear to us what co-methylation patterns normal DNA samples have. Are the co-methylation patterns of the same tissue across several samples different? Are the co-methylation patterns of various tissues of the same sample different? To answer these questions, we conduct analyses using two sets of data: 3-sample-1-tissue (3S1T) and 1-sample-8-tissue (1S8T).ResultsTo study the co-methylation patterns of the two datasets, 3S1T and 1S8T, we investigate the following questions: How often does one methylation state change to other methylation states and how is this change associated with chromosome distance? Based on the 3S1T data, we find there is not significant co-methylation difference among the same spleen tissues of three different samples. However, the analysis results of 1S8T data show that there were significant differences among eight tissues of one sample. For both 3S1T and 1S8T data, we find that the no/low methylation state A and high/full methylation state D tend to remain the same along a chromosome region. We also find that the low/partial methylation state B and partial/high methylation state C tend to change to higher methylation states along a chromosome. Finally, we find that lengths of most co-methylation regions are very short with only a few hundred base pairs. In fact, only a small proportion of methylated regions are longer than 1000 base pairs.ConclusionsIn this paper, we have addressed a few questions regarding within-sample co-methylation patterns in normal tissues. Our statistical analysis results and answers may help researchers to better understand the biological process of DNA methylation. This may pave the way to develop better analysis methods for future methylation research.

Project description:BACKGROUND: The identification of genes that predict in vitro cellular chemosensitivity of cancer cells is of great importance. Chemosensitivity related genes (CRGs) have been widely utilized to guide clinical and cancer chemotherapy decisions. In addition, CRGs potentially share functional characteristics and network features in protein interaction networks (PPIN). METHODS: In this study, we proposed a method to identify CRGs based on Gene Ontology (GO) and PPIN. Firstly, we documented 150 pairs of drug-CCRG (curated chemosensitivity related gene) from 492 published papers. Secondly, we characterized CCRGs from the perspective of GO and PPIN. Thirdly, we prioritized CRGs based on CCRGs' GO and network characteristics. Lastly, we evaluated the performance of the proposed method. RESULTS: We found that CCRG enriched GO terms were most often related to chemosensitivity and exhibited higher similarity scores compared to randomly selected genes. Moreover, CCRGs played key roles in maintaining the connectivity and controlling the information flow of PPINs. We then prioritized CRGs using CCRG enriched GO terms and CCRG network characteristics in order to obtain a database of predicted drug-CRGs that included 53 CRGs, 32 of which have been reported to affect susceptibility to drugs. Our proposed method identifies a greater number of drug-CCRGs, and drug-CCRGs are much more significantly enriched in predicted drug-CRGs, compared to a method based on the correlation of gene expression and drug activity. The mean area under ROC curve (AUC) for our method is 65.2%, whereas that for the traditional method is 55.2%. CONCLUSIONS: Our method not only identifies CRGs with expression patterns strongly correlated with drug activity, but also identifies CRGs in which expression is weakly correlated with drug activity. This study provides the framework for the identification of signatures that predict in vitro cellular chemosensitivity and offers a valuable database for pharmacogenomics research.

Dataset Information

Characterizing genes with distinct methylation patterns in the context of protein-protein interaction network: application to human brain tissues.

Background

Results

Conclusions

Publications

Characterizing genes with distinct methylation patterns in the context of protein-protein interaction network: application to human brain tissues.

Similar Datasets

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