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

TitleDual role of lipids for genome stability and pluripotency facilitates full potency of mouse embryonic stem cells.
Publication TypeJournal Article
Year of Publication2023
AuthorsZhong, L, Gordillo, M, Wang, X, Qin, Y, Huang, Y, Soshnev, A, Kumar, R, Nanjangud, G, James, D, C Allis, D, Evans, T, Carey, B, Wen, D
JournalProtein Cell
Date Published2023 Feb 16
ISSN1674-8018
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.

DOI10.1093/procel/pwad008
Alternate JournalProtein Cell
PubMed ID37029701
Grant ListR01 GM129380-01 / NH / NIH HHS / United States