Modulation of Cell Differentiation and Epigenetic Landscape by Methionine Metabolism

Abstract

Histone modifications are an integral component of epigenetic mechanisms, crucially influencing DNA accessibility and gene expression. These modifications are increasingly recognized as being deeply intertwined with cellular metabolism, particularly through the use of metabolic intermediates as substrates or catalytic cofactors for histone modifiers. This is especially evident in the metabolism of methionine, which significantly affects histone methylation by modulating the availability of substrates for histone methyltransferases. The activities of these enzymes are highly sensitive to substrate concentration due to their unique kinetic properties. Despite some degree of observation and study, the direct impact of methionine availability on specific histone modifications, like H3K36me3, and their ensuing effects on cellular functions have not been extensively explored.To address this knowledge gap, I employed a combination of genetic, biochemical, and pharmacological approaches to examine the consequences of methionine restriction on H3K36me3 and its impact on cellular differentiation. This involved characterizing the dynamics, and reversibility of these processes, and identifying the mediating factors between methionine and cellular differentiation. Our findings highlight a significant dependency of myogenic differentiation on methionine and establish the methionine-SAM-SETD2 pathway as a critical component in this process.This work provides compelling evidence of a connection between nutrient status and cell-fate determination, potentially mediated by histone status. These insights offer new perspectives on the complex interplay between metabolism and epigenetics, laying the foundation for a more profound understanding of how these processes interconnect to influence cellular fate decisions.