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Acute loss of Cited2 impairs Nanog expression and decreases self-renewal of mouse embryonic stem cells.



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Kranc, Kamil R 
Oliveira, Daniel V 
Armesilla-Diaz, Alejandro 
Pacheco-Leyva, Ivette 
Catarina Matias, Ana 


Identifying novel players of the pluripotency gene regulatory network centered on Oct4, Sox2, and Nanog as well as delineating the interactions within the complex network is key to understanding self-renewal and early cell fate commitment of embryonic stem cells (ESC). While overexpression of the transcriptional regulator Cited2 sustains ESC pluripotency, its role in ESC functions remains unclear. Here, we show that Cited2 is important for proliferation, survival, and self-renewal of mouse ESC. We position Cited2 within the pluripotency gene regulatory network by defining Nanog, Tbx3, and Klf4 as its direct targets. We also demonstrate that the defects caused by Cited2 depletion are, at least in part, rescued by Nanog constitutive expression. Finally, we demonstrate that Cited2 is required for and enhances reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells.



Cited2, Nanog, Pluripotency, Self-renewal, Transcriptional regulation, Animals, Cell Differentiation, Cell Proliferation, Embryonic Stem Cells, Gene Regulatory Networks, Homeodomain Proteins, Humans, Kruppel-Like Factor 4, Mice, Nanog Homeobox Protein, Pluripotent Stem Cells, Repressor Proteins, Trans-Activators, Transfection

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Stem Cells

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Oxford University Press (OUP)
Wellcome Trust (097922/Z/11/B)
This work was supported by National Portuguese funding through FCT—Fundac¸~ao para a Ci^encia e a Tecnologia, projects PEst-OE/EQB/LA0023/2013 and PTDC/SAU-ENB/111702/ 2009, the Young investigator award from the C^amara Municipal de Oeiras and an award from the Merck Sharp & Dhome Foundation—Portugal to J.B. K.R.K. is a CRUK Senior Cancer Research Fellow. Work in KRK’s laboratory is funded by CRUK, Leukaemia & Lymphoma Research, the Kay Kendall Leukaemia Fund, the Wellcome Trust, and the Medical Research Council. We thank Shoumo Bhattacharya (University of Oxford) for Cited2 fl/fl mice, Austin Smith (University of Cambridge) for E14TG2A and E14/T cells, pPyCAGIP and pPyCAGIP-Nanog, Tommaso Russo (Universit a degli Studi di Napoli Federico II) for pNanog-luc and pOct4-luc, Marie-Annick Buendia (INSERM, Paul Brousse Hospital) for LTBX3-luc, Rui Jian (Third Military Medical University) for pDoubNeo, and Gustavo Tiscornia (University of Algarve) for LV-Cre2AGFP. J.B. is grateful to Paula Alves for sharing resources and equipment in the Animal Cell Technology group (IBET).