For instance, a key ISC-specific transcription factor Tcf-4, responsible for differentiation of Paneth cells, is found to be downregulated in mucosa of patients with ileal CD, and correlates with compromised alpha defensin production.13 On the epigenetic front, an ISC-predominant histone methyltransferase, SETDB1 has been underlined for its role in epithelial homeostasis. This evidence concerns the gene TCF4 and Cowden disease.