A number of genetic studies reveal that mice with genetic ablation of Caspase-8, Fas associated via death domain (Fadd), or SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in IECs develop spontaneous ileitis and colitis owing to sensitizing cells to RIPK3-mediated necroptosis (22–24). The gene discussed is SETDB1; the disease is Crohn ileitis.