Histone 3 lysine 36 methylation shapes an epigenetic landscape in intestinal stem cell to orchestrate lipid metabolism and prevent cell senescence [CUT&Tag]

The self-renewal capacity and differentiation potential of intestinal stem cells (ISCs) decline with age, leading to a loss of homeostasis and increased susceptibility to intestinal diseases. Despite the established importance of lipid metabolism and epigenetic regulation in ISC function, the molecular mechanisms linking these processes to aging-associated ISC dysfunction remain elusive. Here, we demonstrate that H3K36 methylation, caused by NSD2 or SETD2, is critical to ISC fate. We found that the deficiency of H3K36 methylation results in reduced ISC proliferation and differentiation, disturbs fatty acid metabolism, and induces ISC senescence. This loss leads to increased chromatin accessibility and enhancer activation, impairing the function of the SWI/SNF chromatin remodeling complex and affecting genes expression. Importantly, we find that metabolic intervention can rescue the decline in ISC numbers due to H3K36 methylation deficiency. Our findings reveal a critical role for H3K36 methylation in maintaining epigenetic landscape to orchestrate lipid metabolism and determine intestinal stem cell fate.