Dataset Information

Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells.

ABSTRACT:

Background

Recent work has revealed that a core group of transcription factors (TFs) regulates the key characteristics of embryonic stem (ES) cells: pluripotency and self-renewal. Current efforts focus on identifying genes that play important roles in maintaining pluripotency and self-renewal in ES cells and aim to understand the interactions among these genes. To that end, we investigated the use of unsigned and signed network analysis to identify pluripotency and differentiation related genes.

Results

We show that signed networks provide a better systems level understanding of the regulatory mechanisms of ES cells than unsigned networks, using two independent murine ES cell expression data sets. Specifically, using signed weighted gene co-expression network analysis (WGCNA), we found a pluripotency module and a differentiation module, which are not identified in unsigned networks. We confirmed the importance of these modules by incorporating genome-wide TF binding data for key ES cell regulators. Interestingly, we find that the pluripotency module is enriched with genes related to DNA damage repair and mitochondrial function in addition to transcriptional regulation. Using a connectivity measure of module membership, we not only identify known regulators of ES cells but also show that Mrpl15, Msh6, Nrf1, Nup133, Ppif, Rbpj, Sh3gl2, and Zfp39, among other genes, have important roles in maintaining ES cell pluripotency and self-renewal. We also report highly significant relationships between module membership and epigenetic modifications (histone modifications and promoter CpG methylation status), which are known to play a role in controlling gene expression during ES cell self-renewal and differentiation.

Conclusion

Our systems biologic re-analysis of gene expression, transcription factor binding, epigenetic and gene ontology data provides a novel integrative view of ES cell biology.

SUBMITTER: Mason MJ

PROVIDER: S-EPMC2727539 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Publications

Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells.

Mason Mike J MJ Fan Guoping G Plath Kathrin K Zhou Qing Q Horvath Steve S

BMC genomics 20090720

<h4>Background</h4>Recent work has revealed that a core group of transcription factors (TFs) regulates the key characteristics of embryonic stem (ES) cells: pluripotency and self-renewal. Current efforts focus on identifying genes that play important roles in maintaining pluripotency and self-renewal in ES cells and aim to understand the interactions among these genes. To that end, we investigated the use of unsigned and signed network analysis to identify pluripotency and differentiation relate ...[more]

PMID: 19619308

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Project description:BackgroundUnderstanding the molecular mechanisms controlling pluripotency in embryonic stem cells (ESCs) is of central importance towards realizing their potentials in medicine and science. Cross-species examination of transcriptional co-expression allows elucidation of fundamental and species-specific mechanisms regulating ESC self-renewal or differentiation.Methodology/principal findingsWe examined transcriptional co-expression of ESCs from pathways to global networks under the framework of human-mouse comparisons. Using generalized singular value decomposition and comparative partition around medoids algorithms, evolutionarily conserved and divergent transcriptional co-expression regulating pluripotency were identified from ESC-critical pathways including ACTIVIN/NODAL, ATK/PTEN, BMP, CELL CYCLE, JAK/STAT, PI3K, TGFbeta and WNT. A set of transcription factors, including FOX, GATA, MYB, NANOG, OCT, PAX, SOX and STAT, and the FGF response element were identified that represent key regulators underlying the transcriptional co-expression. By transcriptional intervention conducted in silico, dynamic behavior of pathways was examined, which demonstrate how much and in which specific ways each gene or gene combination effects the behavior transition of a pathway in response to ESC differentiation or pluripotency induction. The global co-expression networks of ESCs were dominated by highly connected hub genes such as IGF2, JARID2, LCK, MYCN, NASP, OCT4, ORC1L, PHC1 and RUVBL1, which are possibly critical in determining the fate of ESCs.Conclusions/significanceThrough these studies, evolutionary conservation at genomic, transcriptomic, and network levels is shown to be an effective predictor of molecular factors and mechanisms controlling ESC development. Various hypotheses regarding mechanisms controlling ESC development were generated, which could be further validated by in vitro experiments. Our findings shed light on the systems-level understanding of how ESC differentiation or pluripotency arises from the connectivity or networks of genes, and provide a "road-map" for further experimental investigation.

Project description:Slow germination speed caused by low temperature stress intensifies the risk posed by adverse environmental factors, contributing to low germination rate and reduced production of rapeseed. The purpose of this study was to understand the transcriptional regulation mechanism for rapid germination of rapeseed. The results showed that seed components and size do not determine the seed germination speed. Different temporal transcriptomic profiles were generated under normal and low temperature conditions in genotypes with fast and slow germination speeds. Using weight gene co-expression network analysis, 37 823 genes were clustered into 15 modules with different expression patterns. There were 10 233 and 9111 differentially expressed genes found to follow persistent tendency of up- and down-regulation, respectively, which provided the conditions necessary for germination. Hub genes in the continuous up-regulation module were associated with phytohormone regulation, signal transduction, the pentose phosphate pathway, and lipolytic metabolism. Hub genes in the continuous down-regulation module were involved in ubiquitin-mediated proteolysis. Through pairwise comparisons, 1551 specific upregulated DEGs were identified for the fast germination speed genotype under low temperature stress. These DEGs were mainly enriched in RNA synthesis and degradation metabolisms, signal transduction, and defense systems. Transcription factors, including WRKY, bZIP, EFR, MYB, B3, DREB, NAC, and ERF, are associated with low temperature stress in the fast germination genotype. The aquaporin NIP5 and late embryogenesis abundant (LEA) protein genes contributed to the water uptake and transport under low temperature stress during seed germination. The ethylene/H2O2-mediated signal pathway plays an important role in cell wall loosening and embryo extension during germination. The ROS-scavenging system, including catalase, aldehyde dehydrogenase, and glutathione S-transferase, was also upregulated to alleviate ROS toxicity in the fast germinating genotype under low temperature stress. These findings should be useful for molecular assisted screening and breeding of fast germination speed genotypes for rapeseed.

Project description:Most sorghum biomass accumulates in stem secondary cell walls (SCW). As sorghum stems are used as raw materials for various purposes such as feed, energy and fiber reinforced polymers, identifying the genes responsible for SCW establishment is highly important. Taking advantage of studies performed in model species, most of the structural genes contributing at the molecular level to the SCW biosynthesis in sorghum have been proposed while their regulatory factors have mostly not been determined. Validation of the role of several MYB and NAC transcription factors in SCW regulation in Arabidopsis and a few other species has been provided. In this study, we contributed to the recent efforts made in grasses to uncover the mechanisms underlying SCW establishment. We reported updated phylogenies of NAC and MYB in 9 different species and exploited findings from other species to highlight candidate regulators of SCW in sorghum. We acquired expression data during sorghum internode development and used co-expression analyses to determine groups of co-expressed genes that are likely to be involved in SCW establishment. We were able to identify two groups of co-expressed genes presenting multiple evidences of involvement in SCW building. Gene enrichment analysis of MYB and NAC genes provided evidence that while NAC SECONDARY WALL THICKENING PROMOTING FACTOR NST genes and SECONDARY WALL-ASSOCIATED NAC DOMAIN PROTEIN gene functions appear to be conserved in sorghum, NAC master regulators of SCW in sorghum may not be as tissue compartmentalized as in Arabidopsis. We showed that for every homolog of the key SCW MYB in Arabidopsis, a similar role is expected for sorghum. In addition, we unveiled sorghum MYB and NAC that have not been identified to date as being involved in cell wall regulation. Although specific validation of the MYB and NAC genes uncovered in this study is needed, we provide a network of sorghum genes involved in SCW both at the structural and regulatory levels.

Dataset Information

Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells.

Background

Results

Conclusion

Publications

Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells.

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