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

Liangwen Zhong; Miriam Gordillo; Xingyi Wang; Yiren Qin; Yuanyuan Huang; Alexey Soshnev; Ritu Kumar; Gouri Nanjangud; Daylon James; C David Allis; Todd Evans; Bryce Carey; Duancheng Wen

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

Author: Liangwen ZHONG ¹ ; Miriam GORDILLO ² ; Xingyi WANG ³ ; Yiren QIN ¹ ; Yuanyuan HUANG ¹ ; Alexey SOSHNEV ⁴ ; Ritu KUMAR ² ; Gouri NANJANGUD ⁵ ; Daylon JAMES ¹ ; C DAVID ALLIS ⁴ ; Todd EVANS ² ; Bryce CAREY ⁴ ; Duancheng WEN ¹
Author Information

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. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
4. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
5. Molecular Cytogenetics Core. Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: 2i medium; X chromosome loss; developmental potency; female all-ESC mice; genomic stability; lipids; mouse pluripotent stem cells; nucleotide pool depletion; pluripotency transition
MeSH: Male; Animals; Female; Mice; Mouse Embryonic Stem Cells; Embryonic Stem Cells; Genomic Instability; Lipids; DNA/metabolism*; Cell Differentiation
From: Protein & Cell 2023;14(8):591-602
CountryChina
Language:English
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.