title: Embryonic stem cell-specific microRNAs contribute to pluripotency by inhibiting regulators of multiple differentiation pathways.
abstract: The findings that microRNAs (miRNAs) are essential for early development in many species and that embryonic miRNAs can reprogram somatic cells into induced pluripotent stem cells suggest that these miRNAs act directly on transcriptional and chromatin regulators of pluripotency. To elucidate the transcription regulatory networks immediately downstream of embryonic miRNAs, we extended the motif activity response analysis approach that infers the regulatory impact of both transcription factors (TFs) and miRNAs from genome-wide expression states. Applying this approach to multiple experimental data sets generated from mouse embryonic stem cells (ESCs) that did or did not express miRNAs of the ESC-specific miR-290-295 cluster, we identified multiple TFs that are direct miRNA targets, some of which are known to be active during cell differentiation. Our results provide new insights into the transcription regulatory network downstream of ESC-specific miRNAs, indicating that these miRNAs act on cell cycle and chromatin regulators at several levels and downregulate TFs that are involved in the innate immune response.
authors.affiliation: Biozentrum, University of Basel, Klingelberstrasse 50-70, CH-4056 Basel, Switzerland.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Gruber
authors.affiliation: Biozentrum, University of Basel, Klingelberstrasse 50-70, CH-4056 Basel, Switzerland.
authors.forename: William A
authors.initials: WA
authors.lastname: Grandy
authors.affiliation: Biozentrum, University of Basel, Klingelberstrasse 50-70, CH-4056 Basel, Switzerland.
authors.forename: Piotr J
authors.initials: PJ
authors.lastname: Balwierz
authors.affiliation: Biozentrum, University of Basel, Klingelberstrasse 50-70, CH-4056 Basel, Switzerland.
authors.forename: Yoana A
authors.initials: YA
authors.lastname: Dimitrova
authors.affiliation: Biozentrum, University of Basel, Klingelberstrasse 50-70, CH-4056 Basel, Switzerland.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pachkov
authors.affiliation: ETH Zürich, Otto-Stern-Weg 7, CH-8093 Zürich, Switzerland.
authors.forename: Constance
authors.initials: C
authors.lastname: Ciaudo
authors.affiliation: Biozentrum, University of Basel, Klingelberstrasse 50-70, CH-4056 Basel, Switzerland.
authors.forename: Erik van
authors.initials: Ev
authors.lastname: Nimwegen
authors.affiliation: Biozentrum, University of Basel, Klingelberstrasse 50-70, CH-4056 Basel, Switzerland mihaela.zavolan@unibas.ch.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Zavolan
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks; D050836:Interferon Regulatory Factor-2 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D050836:Interferon Regulatory Factor-2; D035683:MicroRNAs; D051996:Transcription Factor RelA