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Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells.

ABSTRACT: Networks of transcription factors (TFs) are thought to determine and maintain the identity of cells. Here we systematically repressed each of 100 TFs with shRNA and carried out global gene expression profiling in mouse embryonic stem (ES) cells. Unexpectedly, only the repression of a handful of TFs significantly affected transcriptomes, which changed in two directions/trajectories: one trajectory by the repression of either Pou5f1 or Sox2; the other trajectory by the repression of either Esrrb, Sall4, Nanog, or Tcfap4. The data suggest that the trajectories of gene expression change are already preconfigured by the gene regulatory network and roughly correspond to extraembryonic and embryonic fates of cell differentiation, respectively. These data also indicate the robustness of the pluripotency gene network, as the transient repression of most TFs did not alter the transcriptomes.

SUBMITTER: Nishiyama A

PROVIDER: S-EPMC3589720 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells.

Nishiyama Akira A Sharov Alexei A AA Piao Yulan Y Amano Misa M Amano Tomokazu T Hoang Hien G HG Binder Bernard Y BY Tapnio Richard R Bassey Uwem U Malinou Justin N JN Correa-Cerro Lina S LS Yu Hong H Xin Li L Meyers Emily E Zalzman Michal M Nakatake Yuhki Y Stagg Carole C Sharova Lioudmila L Qian Yong Y Dudekula Dawood D Sheer Sarah S Cadet Jean S JS Hirata Tetsuya T Yang Hsih-Te HT Goldberg Ilya I Evans Michele K MK Longo Dan L DL Schlessinger David D Ko Minoru S H MS

Scientific reports 20130101

Networks of transcription factors (TFs) are thought to determine and maintain the identity of cells. Here we systematically repressed each of 100 TFs with shRNA and carried out global gene expression profiling in mouse embryonic stem (ES) cells. Unexpectedly, only the repression of a handful of TFs significantly affected transcriptomes, which changed in two directions/trajectories: one trajectory by the repression of either Pou5f1 or Sox2; the other trajectory by the repression of either Esrrb, ...[more]

PMID: 23462645

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Project description:BackgroundTo understand the gene regulatory system that governs the self-renewal and pluripotency of embryonic stem cells (ESCs) is an important step for promoting regenerative medicine. In it, the role of several core transcription factors (TFs), such as Oct4, Sox2 and Nanog, has been intensively investigated, details of their involvement in the genome-wide gene regulation are still not well clarified.MethodsWe constructed a predictive model of genome-wide gene expression in mouse ESCs from publicly available ChIP-seq data of 12 core TFs. The tag sequences were remapped on the genome by various alignment tools. Then, the binding density of each TF is calculated from the genome-wide bona fide TF binding sites. The TF-binding data was combined with the data of several epigenetic states (DNA methylation, several histone modifications, and CpG island) of promoter regions. These data as well as the ordinary peak intensity data were used as predictors of a simple linear regression model that predicts absolute gene expression. We also developed a pipeline for analyzing the effects of predictors and their interactions.ResultsThrough our analysis, we identified two classes of genes that are either well explained or inefficiently explained by our model. The latter class seems to be genes that are not directly regulated by the core TFs. The regulatory regions of these gene classes show apparently distinct patterns of DNA methylation, histone modifications, existence of CpG islands, and gene ontology terms, suggesting the relative importance of epigenetic effects. Furthermore, we identified statistically significant TF interactions correlated with the epigenetic modification patterns.ConclusionsHere, we proposed an improved prediction method in explaining the ESC-specific gene expression. Our study implies that the majority of genes are more or less directly regulated by the core TFs. In addition, our result is consistent with the general idea of relative importance of epigenetic effects in ESCs.

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Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells.

Publications

Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells.

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