Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming [ES_H3K9ac_ChIP-seq]

Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here, we show that nuclear lamina dynamics regulate cysteine catabolic flux, crucial for proper stem cell fate and longevity. Lamin A/C loss in naïve pluripotent stem cells upregulates CTH and CBS enzyme expression, promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naïve to primed pluripotency and abnormal cell fate. Conversely, gain-of-function mutation of lamin A/C, associated with premature aging, reduces CTH and CBS levels. This reroutes the cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Importantly, modulation of cysteine metabolism rescues the abnormal cell fate, DNA damage repair defects, and the senescent phenotype upon lamin A/C mutation, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases. Overall design: PLKO_LmnaKO,LmnaKO_shCbs and LmnaKO_shCth Nkx2-5-GFP mES cell lines were cultured on feeder condition in DMEM high glucose supplemented with 15% FCS and 1000 U/ml LIF. ESCs were harvested to perform for H3K9ac ChIP-seq.