Collaborative rewiring of the pluripotency network by chromatin and signalling modulating pathways

Khoa A. Tran, Steven A. Jackson, Zachariah P.G. Olufs, Nur Zafirah Zaidan, Ning Leng, Christina Kendziorski, Sushmita Roy and Rupa Sridharan ()
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Khoa A. Tran: Wisconsin Institute for Discovery, University of Wisconsin
Steven A. Jackson: Wisconsin Institute for Discovery, University of Wisconsin
Zachariah P.G. Olufs: Wisconsin Institute for Discovery, University of Wisconsin
Nur Zafirah Zaidan: Wisconsin Institute for Discovery, University of Wisconsin
Ning Leng: University of Wisconsin
Christina Kendziorski: University of Wisconsin
Sushmita Roy: Wisconsin Institute for Discovery, University of Wisconsin
Rupa Sridharan: Wisconsin Institute for Discovery, University of Wisconsin

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) represents a profound change in cell fate. Here, we show that combining ascorbic acid (AA) and 2i (MAP kinase and GSK inhibitors) increases the efficiency of reprogramming from fibroblasts and synergistically enhances conversion of partially reprogrammed intermediates to the iPSC state. AA and 2i induce differential transcriptional responses, each leading to the activation of specific pluripotency loci. A unique cohort of pluripotency genes including Esrrb require both stimuli for activation. Temporally, AA-dependent histone demethylase effects are important early, whereas Tet enzyme effects are required throughout the conversion. 2i function could partially be replaced by depletion of components of the epidermal growth factor (EGF) and insulin growth factor pathways, indicating that they act as barriers to reprogramming. Accordingly, reduction in the levels of the EGF receptor gene contributes to the activation of Esrrb. These results provide insight into the rewiring of the pluripotency network at the late stage of reprogramming.

Date: 2015
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DOI: 10.1038/ncomms7188

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