Dual role of lipids for genome stability and pluripotency facilitates full potency of mouse embryonic stem cells

doi:10.1093/procel/pwad008

Protein Cell

2023, Vol. 14

Issue (8) : 591-602 https://doi.org/10.1093/procel/pwad008

RESEARCH ARTICLE

Dual role of lipids for genome stability and pluripotency facilitates full potency of mouse embryonic stem cells

Liangwen Zhong¹, Miriam Gordillo², Xingyi Wang⁴, Yiren Qin¹, Yuanyuan Huang¹, Alexey Soshnev^3,⁶, Ritu Kumar^2,⁷, Gouri Nanjangud⁵, Daylon James¹, C. David Allis³, Todd Evans²(

), Bryce Carey³(

), Duancheng Wen¹(

)

¹. Department of Reproductive Medicine, Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10065, USA
². Department of Surgery, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA
³. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA
⁴. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
⁵. Molecular Cytogenetics Core. Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
⁶. Department of Neuroscience, Developmental and Regenerative Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA
⁷. Gladstone Institutes, 1650 Owens St, San Francisco, CA 94158, USA

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Abstract

While Mek1/2 and Gsk3β inhibition (“2i”) supports the maintenance of murine embryonic stem cells (ESCs) in a homogenous naïve state, prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential. Additionally, 2i fails to support derivation and culture of fully potent female ESCs. Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin (AlbuMAX) undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture. Mechanistically, lipids in AlbuMAX impact intracellular metabolism including nucleotide biosynthesis, lipid biogenesis, and TCA cycle intermediates, with enhanced expression of DNMT3s that prevent DNA hypomethylation. Lipids induce a formative-like pluripotent state through direct stimulation of Erk2 phosphorylation, which also alleviates X chromosome loss in female ESCs. Importantly, both male and female “all-ESC” mice can be generated from de novo derived ESCs using AlbuMAX-based media. Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.

Keywords mouse pluripotent stem cells lipids pluripotency transition genomic stability developmental potency nucleotide pool depletion 2i medium X chromosome loss female all-ESC mice

Corresponding Author(s): Todd Evans,Bryce Carey,Duancheng Wen

Issue Date: 26 September 2023

Cite this article:

Liangwen Zhong,Miriam Gordillo,Xingyi Wang, et al. Dual role of lipids for genome stability and pluripotency facilitates full potency of mouse embryonic stem cells[J]. Protein Cell, 2023, 14(8): 591-602.

URL:

https://academic.hep.com.cn/pac/EN/10.1093/procel/pwad008
https://academic.hep.com.cn/pac/EN/Y2023/V14/I8/591

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