NSD2 links developmental plasticity to mitochondrial function in muscle and lymphocyte differentiation

Developmental processes require a precise regulation of all the aspects of cellular function to successfully achieve the generation of differentiated cells. This regulation does not only encompass gene expression levels activating the developmental programs, but should also attend the demanding energetic needs of the differentiating cells. Epigenetic regulators are essential for establishing cell-type-specific transcriptional programs, but emerging evidence suggests that they also play a more direct role in regulating metabolism. Nsd2 is a Histone-3-Lysine36 mono- and di-methyltransferase key in the development of several cell types, and is involved in human pathologies both by loss- and gain-of-function alterations. Methylation at H3K36 by proteins of the Nsd family has been shown to be crucial in the maintenance of cell identity by being involved in the establishment and sustained expression of cell-type-specific programs. Here, we demonstrate that Nsd2 is essential for coordinating mitochondrial function and metabolic remodeling during B cell activation and muscle progenitor differentiation. In the terminal differentiation of B cells in the germinal center, the absence of Nsd2 results in defective mitochondrial function, characterized by hyperpolarization of the mitochondrial membrane, elevated reactive oxygen species (ROS) production, and reduced oxygen consumption and ATP production. Similarly, Nsd2 deficiency in myoblasts disrupts metabolic reprogramming during muscle differentiation, leading to impaired mitochondrial respiration and structural abnormalities. In both cell types, these alterations correlate with widespread changes in the expression of genes involved in mitochondrial function and cellular metabolism. These findings highlight Nsd2 as a central mediator linking epigenetic regulation with mitochondrial function, underscoring its critical role in coupling transcriptional programs with metabolic adaptation during cell differentiation.