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TG-interacting factor1 (Tgif1) maintains the identity of mouse ES cells by counterbalancing the expression of ES cell core factors

ABSTRACT: TG-interacting factor1 (Tgif1) is well-known as a transcriptional repressor in transforming growth factor beta (TGFβ) signaling pathway. Target mapping of ES cell core factors in mouse embryonic stem (ES) cells revealed that Tgif1 is occupied by Oct4 and Nanog. Moreover, recent interactome study of mouse gene regulatory regions showed a preferential regulation of Tgif1 by mouse ES cell specific enhancers. However, the detailed role and mode of actions of Tgif1 in stem cell maintenance and development remains elusive. We show that Tgif1 is indispensable for self-renewal and pluripotency of mouse embryonic stem (ES) cells. Aberrant expression of Tgif1 promotes differentiation of ES cells even in the presence of LIF in part by deregulation of pluripotency factors. Intriguingly, we find that Tgif1 level is a critical factor to determine specific lineage commitment in a dosage-dependent manner. We further show that Tgif1 interacts with ES cell core factors and co-localizes at their binding sites, which eventually restricts expression of ES cell core factors including Oct4, Sox2, and Nanog. Taken together, we provide new insights into the roles of Tgif1 in maintenance as well as differentiation of ES cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE55404 | GEO | 2015/09/26

SECONDARY ACCESSION(S): PRJNA239579

REPOSITORIES: GEO

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Project description:Chavez2009 - a core regulatory network of OCT4 in human embryonic stem cells A core OCT4-regulated network has been identified as a test case, to analyase stem cell characteristics and cellular differentiation. This model is described in the article: In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach. Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R BMC Genomics, 2009, 10:314 Abstract: BACKGROUND: The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency. RESULTS: We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 - 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a de novo motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation. CONCLUSION: Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The de novo motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies. This model is hosted on BioModels Database and identified by: MODEL1305010000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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TG-interacting factor1 (Tgif1) maintains the identity of mouse ES cells by counterbalancing the expression of ES cell core factors

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