LIF-activated Jak signaling determines Esrrb expression during late-stage reprogramming.

Delun Huang,Ling Wang,Ming Zhang,Jingyue Duan,Chang Huang,Xiuchun (Cindy) Tian,Young Tang

doi:10.1242/bio.029264

Delun Huang, Ling Wang + Show 5 more

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https://doi.org/10.1242/bio.029264

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Journal: Biology open	Publication Date: Jan 1, 2017
Citations: 14	License type: CC BY 3.0

Affiliation: Guangxi University, University of Connecticut

Abstract

ABSTRACTThe regulatory process of naïve-state induced pluripotent stem cell (iPSC) generation is not well understood. Leukemia inhibitory factor (LIF)-activated Janus kinase/signal transducer and activator of transcription 3 (Jak/Stat3) is the master regulator for naïve-state pluripotency achievement and maintenance. The estrogen-related receptor beta (Esrrb) serves as a naïve-state marker gene regulating self-renewal of embryonic stem cells (ESCs). However, the interconnection between Esrrb and LIF signaling for pluripotency establishment in reprogramming is unclear. We screened the marker genes critical for complete reprogramming during mouse iPSC generation, and identified genes including Esrrb that are responsive to LIF/Jak pathway signaling. Overexpression of Esrrb resumes the reprogramming halted by inhibition of Jak activity in partially reprogrammed cells (pre-iPSCs), and leads to the generation of pluripotent iPSCs. We further show that neither overexpression of Nanog nor stimulation of Wnt signaling, two upstream regulators of Esrrb in ESCs, stimulates the expression of Esrrb in reprogramming when LIF or Jak activity is blocked. Our study demonstrates that Esrrb is a specific reprogramming factor regulated downstream of the LIF/Jak signaling pathway. These results shed new light on the regulatory role of LIF pathway on complete pluripotency establishment during iPSC generation.

Highlights

Generation of induced pluripotent stem cells (Takahashi and Yamanaka, 2006) leads to the establishment of pluripotency equivalent to embryonic stem cells (ESCs) without embryo destruction, by overexpressing the so-called Yamanaka factors, namely Oct4, Klf4, Sox2 and c-Myc (OKSM)
We describe the identification of estrogen-related receptor beta (Esrrb) as an important effector downstream of leukemia inhibitory factor (LIF)/ Jak/Stat3 signaling for completely reprogrammed induced pluripotent stem cell (iPSC) generation, with its expression dependent on LIF pathway activation
Esrrb is activated by LIF/Jak signaling during the reprogramming process Previous studies of reprogramming dynamics towards naïve-state pluripotency have identified a number of pluripotent genes for which expression in reprogramming stringently marks the development to pluripotent iPSC state (Buganim et al, 2012; Polo et al, 2012)

Summary

Introduction

Generation of induced pluripotent stem cells (iPSCs) (Takahashi and Yamanaka, 2006) leads to the establishment of pluripotency equivalent to embryonic stem cells (ESCs) without embryo destruction, by overexpressing the so-called Yamanaka factors, namely Oct, Klf, Sox and c-Myc (OKSM). A number of genes have been reported to be regulated by Stat and mediate LIFindependent mouse ESC self-renewal or iPSC reprogramming. These include MnSOD, Klf, Klf, Nanog, Gbx, Pim, Pim, Pramel, Tfcp2l1, c-Myc and Foxm (Aksoy et al, 2007; Cartwright et al, 2005; Casanova et al, 2011; Festuccia et al, 2012; Hall et al, 2009; Martello et al, 2013; Niwa et al, 2009; Parisi et al, 2008; Sheshadri et al, 2015; Tai and Ying, 2013; Tan et al, 2014; Ye et al, 2013). A better understanding of the Stat3regulated downstream targets/effectors is necessary, and will further facilitate the naïve-state iPSC generation across different species including humans (De Los Angeles et al, 2012)

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