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DNA methylation is indispensable for leukemia inhibitory factor dependent embryonic stem cells reprogramming

By Baojiang Wu, Yunxia Li, Bojiang Li, Baojing Zhang, Yanqiu Wang, Lin Li, Junpeng Gao, Yuting Fu, Shudong Li, Chen Chen, M. Azim Surani, Fuchou Tang, Xihe Li, Siqin Bao

Posted 18 Mar 2020
bioRxiv DOI: 10.1101/2020.03.17.994939

Naive pluripotency can be maintained by the 2i/LIF supplements (CHIR99021, PD0325901 and LIF), which primarily affect canonical WNT, FGF/ERK, and JAK/STAT3 signaling. However, whether one of these tripartite supplements alone is sufficient to maintain naive self-renewal remain unclear. Here we show that LIF alone is sufficient to induce reprogramming of 2i/LIF cultured ESCs (2i/L-ESCs) to ESCs with hypermethylated state (L-ESCs). In vitro, upon withdrawal of 2i, 2i/L-ESCs overcome the epigenetic barrier and DNA hypermethylated, which accompanies transcriptional changes and subsequent establishment of epigenetic memory. Global transcriptome features also show that L-ESCs are close to 2i/L-ESCs and in a stable state between naive and primed pluripotency. Notably, our results demonstrate that DNA methylation is indispensable for LIF-dependent mouse ESCs reprogramming and self-renew. LIF-dependent ESCs reprogramming efficiency is significantly increased in serum treatment and reduced in Dnmt3a or Dnmt3l knockout ESCs. Importantly, unlike epiblast and EpiSCs, L-ESCs contribute to somatic tissues and germ cells in chimaeras. Such simple culture system of ESCs is more conducive to clarify the molecular mechanism of ESCs in vitro culture. ### Competing Interest Statement The authors have declared no competing interest.

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