Histone Lysine Methyltransferases in Kidney Development and Disease

Histone lysine methyltransferases (KMTs) regulate chromatin states that control gene expression during development and disease. In the kidney, emerging evidence links KMT-dependent histone methylation to nephrogenesis, podocyte integrity, diabetic kidney disease, acute kidney injury, renal fibrosis, polycystic kidney disease, and renal cancer. Human genetic studies further support a developmental role for KMTs, as pathogenic variants in KMT2D, NSD1, EHMT1, and related chromatin regulators are associated with syndromic renal and urinary tract abnormalities. Mechanistic studies implicate EZH2, DOT1L, SETD2, G9a, SETDB1, SETD7, KMT2A, and SMYD2 in podocyte injury, tubular stress responses, and fibrotic remodeling. However, the renal cell-specific functions and relevant substrates of many KMTs remain incompletely defined. This review compares clinical associations, experimental KMT dependence, and locus-specific chromatin evidence across renal compartments. The synthesis identifies a central limitation: the renal effect of a KMT cannot be inferred from its associated histone mark alone, and beneficial inhibition in one setting may conflict with protective functions in another. We integrate representative mechanisms, evaluate the limits of experimental models, and outline priorities for human renal validation and cell-specific therapeutic development.