Leech, C. M. | bioRxiv Science

bioRxiv2026

Methionine, Not S-adenosylmethionine, Acts as a Primary Metabolic Stress Signal for Chromatin Remodeling

Epigenetic regulation is tightly linked to cellular metabolism through chromatin-modifying enzymes that depend on central metabolites as co-substrates. Methionine is an essential amino acid that is directly converted by methionine adenosyltransferase 2A (MAT2A) into S-adenosylmethionine (SAM), the universal methyl donor required for histone and DNA methylation. Although methionine restriction/depletion can alter the chromatin methylation landscape and improve physiological outcomes in diverse biological systems, it remains unclear whether these effects arise from loss of methionine itself or from secondary depletion of SAM. Here, we show that methionine depletion induces nuclear accumulation of MAT2A together with redistribution of H3K9 methylation, derepression of transposable elements, activation of stress-response pathways, and broad transcriptional reprogramming. Surprisingly, pharmacologic inhibition reduced intracellular SAM to levels comparable to methionine depletion but failed to reproduce these major epigenetic or transcriptional responses. Furthermore, depletion of the SAM-sensor SAMTOR and inhibition of KDM4 histone demethylases did not prevent methionine-dependent chromatin remodeling, indicating that canonical SAM-sensing pathways are not required for this adaptation. Instead, methionine depletion uniquely induced innate immune and integrated stress-response programs consistent with a viral mimicry-like state. These findings demonstrate that methionine availability, rather than SAM abundance, functions as a primary metabolic signal regulating epigenetic adaptation to nutrient stress. Our data support a model in which methionine is sensed independently of SAM abundance and acts upstream of stress signaling pathways that secondarily remodel chromatin.

biochemistry↗

bioRxiv2019

The coordinate actions of calcineurin and Hog1 mediate the response to cellular stress through multiple nodes of the cell cycle network

Upon exposure to environmental stressors, cells transiently arrest the cell cycle while they adapt and restore homeostasis. A challenge for all cells is to distinguish between diverse stress signals and coordinate the appropriate adaptive response with cell cycle arrest. Here we investigate the role of the stress-activated phosphatase calcineurin (CN) in this process and show that CN utilizes multiple pathways to control the cell cycle. Upon activation, CN inhibits transcription factors (TFs) that regulate the G1/S transition through activation of the stress-activated MAPK Hog1. In contrast, CN inactivates G2/M TFs through a combination of Hog1-dependent and -independent mechanisms. These findings demonstrate that CN and Hog1 act in a coordinated manner at multiple nodes of the cell cycle-regulatory network to rewire gene expression and arrest cells in response to stress. Our results suggest that crosstalk between CN and stress-activated MAPKs helps cells tailor their adaptive responses to specific stressors.

cell biology↗