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Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming

Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to u...

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Main Authors: Wang, Yinuo (Author) , Shi, Haojie (Author) , Wittig, Janina (Author) , Ren, Yonggang (Author) , Cordero, Julio (Author) , Dewenter, Matthias (Author) , Mella, Jessica (Author) , Buchwalter, Abigail (Author) , Backs, Johannes (Author) , Wieland, Thomas (Author) , Heineke, Jörg (Author) , Fleming, Ingrid (Author) , Bibli, Sofia-Iris (Author) , Dobreva, Gergana (Author)
Format: Article (Journal)
Language:English
Published: 28 January 2026
In: Nature metabolism
Year: 2026, Volume: 8, Issue: 2, Pages: 431-453
ISSN:2522-5812
DOI:10.1038/s42255-025-01443-2
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s42255-025-01443-2
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s42255-025-01443-2
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Author Notes:Yinuo Wang, Haojie Shi, Janina Wittig, Yonggang Ren, Julio Cordero, Matthias Dewenter, Jessica Mella, Abigail Buchwalter, Johannes Backs, Thomas Wieland, Joerg Heineke, Ingrid Fleming, Sofia-Iris Bibli & Gergana Dobreva
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Summary:Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.
Item Description:Im Anhang 23 ungezählte Seiten
Gesehen am 27.04.2026
Physical Description:Online Resource
ISSN:2522-5812
DOI:10.1038/s42255-025-01443-2

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