Recent studies show that the short‐chain lysine acylations on histone proteins are regulated by intracellular short‐chain fatty acids and their corresponding acyl‐CoAs.[1] These histone PTMs modulate chromatin structure and gene expression.[1] They are closely associated with different diseases, such as cancer and metabolic diseases, and physiological changes (such as fasting).[19, 20] Therefore, a metabolite‐regulated PTM offers a potential feedback mechanism to couple cellular metabolism with gene expression. The gene discussed is H2BC12L; the disease is metabolic disease.