The diverse effects on fundamental processes including epithelial differentiation, metabolism, immune response and microbiome colonization, all brought about by a single amino acid modification S89A, highlights the critical role of this region in p300 as a signaling nexus in development and disease (e.g., inflammation and cancer) and the rationale for conservation of this residue and surrounding region for hundreds of million years of vertebrate evolution. The gene discussed is EP300; the disease is cancer.