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TGF-? stimulation in human and murine cells reveals commonly affected biological processes and pathways at transcription level.

ABSTRACT: The TGF-? signaling pathway is a fundamental pathway in the living cell, which plays a key role in many central cellular processes. The complex and sometimes contradicting mechanisms by which TGF-? yields phenotypic effects are not yet completely understood. In this study we investigated and compared the transcriptional response profile of TGF-?1 stimulation in different cell types. For this purpose, extensive experiments are performed and time-course microarray data are generated in human and mouse parenchymal liver cells, human mesenchymal stromal cells and mouse hematopoietic progenitor cells at different time points. We applied a panel of bioinformatics methods on our data to uncover common patterns in the dynamic gene expression response in respective cells.Our analysis revealed a quite variable and multifaceted transcriptional response profile of TGF-?1 stimulation, which goes far beyond the well-characterized classical TGF-?1 signaling pathway. Nonetheless, we could identify several commonly affected processes and signaling pathways across cell types and species. In addition our analysis suggested an important role of the transcription factor EGR1, which appeared to have a conserved influence across cell-types and species. Validation via an independent dataset on A549 lung adenocarcinoma cells largely confirmed our findings. Network analysis suggested explanations, how TGF-?1 stimulation could lead to the observed effects.The analysis of dynamical transcriptional response to TGF-? treatment experiments in different human and murine cell systems revealed commonly affected biological processes and pathways, which could be linked to TGF-?1 via network analysis. This helps to gain insights about TGF-? pathway activities in these cell systems and its conserved interactions between the species and tissue types.

SUBMITTER: Abnaof K

PROVIDER: S-EPMC4049504 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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TGF-β stimulation in human and murine cells reveals commonly affected biological processes and pathways at transcription level.

Abnaof Khalid K Mallela Nikhil N Walenda Gudrun G Meurer Steffen K SK Seré Kristin K Lin Qiong Q Smeets Bert B Hoffmann Kurt K Wagner Wolfgang W Zenke Martin M Weiskirchen Ralf R Fröhlich Holger H

BMC systems biology 20140515

<h4>Background</h4>The TGF-β signaling pathway is a fundamental pathway in the living cell, which plays a key role in many central cellular processes. The complex and sometimes contradicting mechanisms by which TGF-β yields phenotypic effects are not yet completely understood. In this study we investigated and compared the transcriptional response profile of TGF-β1 stimulation in different cell types. For this purpose, extensive experiments are performed and time-course microarray data are gener ...[more]

PMID: 24886091

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Project description:Endogenous retroviruses and retrotransposons also termed retroelements (REs) are mobile genetic elements that were active until recently in human genome evolution. REs regulate gene expression by actively reshaping chromatin structure or by directly providing transcription factor binding sites (TFBSs). We aimed to identify molecular processes most deeply impacted by the REs in human cells at the level of TFBS regulation. By using ENCODE data, we identified ~2 million TFBS overlapping with putatively regulation-competent human REs located in 5-kb gene promoter neighborhood (~17% of all TFBS in promoter neighborhoods; ~9% of all RE-linked TFBS). Most of REs hosting TFBS were highly diverged repeats, and for the evolutionary young (0-8% diverged) elements we identified only ~7% of all RE-linked TFBS. The gene-specific distributions of RE-linked TFBS generally correlated with the distributions for all TFBS. However, several groups of molecular processes were highly enriched in the RE-linked TFBS regulation. They were strongly connected with the immunity and response to pathogens, with the negative regulation of gene transcription, ubiquitination, and protein degradation, extracellular matrix organization, regulation of STAT signaling, fatty acids metabolism, regulation of GTPase activity, protein targeting to Golgi, regulation of cell division and differentiation, development and functioning of perception organs and reproductive system. By contrast, the processes most weakly affected by the REs were linked with the conservative aspects of embryo development. We also identified differences in the regulation features by the younger and older fractions of the REs. The regulation by the older fraction of the REs was linked mainly with the immunity, cell adhesion, cAMP, IGF1R, Notch, Wnt, and integrin signaling, neuronal development, chondroitin sulfate and heparin metabolism, and endocytosis. The younger REs regulate other aspects of immunity, cell cycle progression and apoptosis, PDGF, TGF beta, EGFR, and p38 signaling, transcriptional repression, structure of nuclear lumen, catabolism of phospholipids, and heterocyclic molecules, insulin and AMPK signaling, retrograde Golgi-ER transport, and estrogen signaling. The immunity-linked pathways were highly represented in both categories, but their functional roles were different and did not overlap. Our results point to the most quickly evolving molecular pathways in the recent and ancient evolution of human genome.

Project description:The importance of mesenchymal stem cells (MSC) for bone regeneration is growing. Among MSC the bone marrow-derived stem cells (BMSC) are considered the gold standard in tissue engineering and regenerative medicine; however, the adipose-derived stem cells (ASC) have very similar properties and some advantages to be considered a good alternative to BMSC. The molecular mechanisms driving adipogenesis are relatively well-known but mechanisms driving osteogenesis are poorly known, particularly in pig. In the present study we have used transcriptome analysis to unravel pathways and biological functions driving in vitro adipogenesis and osteogenesis in BMSC and ASC. The analysis was performed using the novel Dynamic Impact Approach and functional enrichment analysis. In addition, a k-mean cluster analysis in association with enrichment analysis, networks reconstruction, and transcription factors overlapping analysis were performed in order to uncover the coordination of biological functions underlining differentiations. Analysis indicated a larger and more coordinated transcriptomic adaptation during adipogenesis compared to osteogenesis, with a larger induction of metabolism, particularly lipid synthesis (mostly triglycerides), and a larger use of amino acids for synthesis of feed-forward adipogenic compounds, larger cell signaling, lower cell-to-cell interactions, particularly for the cytoskeleton organization and cell junctions, and lower cell proliferation. The coordination of adipogenesis was mostly driven by Peroxisome Proliferator-activated Receptors together with other known adipogenic transcription factors. Only a few pathways and functions were more induced during osteogenesis compared to adipogenesis and some were more inhibited during osteogenesis, such as cholesterol and protein synthesis. Up-stream transcription factor analysis indicated activation of several lipid-related transcription regulators (e.g., PPARs and CEBP?) during adipogenesis but osteogenesis was driven by inhibition of several up-stream regulators, such as MYC. Between MSCs the data indicated an 'adipocyte memory' in ASC with also an apparent lower immunogenicity compared to BMSC during differentiations. Overall the analysis allowed proposing a dynamic model for the adipogenic and osteogenic differentiation in porcine ASC and BMSC.

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TGF-? stimulation in human and murine cells reveals commonly affected biological processes and pathways at transcription level.

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TGF-β stimulation in human and murine cells reveals commonly affected biological processes and pathways at transcription level.

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