Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming [ES_ChIP_seq_H3K9me3_LA]

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 naïve 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 naïve 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 aging, 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. Importantly, 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.