HCFC2 (host cell factor C2) is a chr12-associated transcriptional regulator that plays distinct roles from its paralog HCF-1. HCFC2 functions as a component of histone methyltransferase complexes, specifically interacting with MLL through a conserved binding motif to regulate gene expression 1. Unlike HCF-1, HCFC2 localizes to nucleoli and inhibits cell proliferation while promoting differentiation gene expression programs 2. HCFC2 is essential for innate immune responses, facilitating IRF1 and IRF2 binding to promoters of interferon-regulated genes including TLR3, and is required for effective responses to viral infections such as influenza and herpes simplex virus 3. The protein can stabilize VP16-induced transcriptional complexes, though with reduced transcriptional activity compared to HCF-1 4. HCFC2 expression correlates with behavioral flexibility in reversal learning tasks, suggesting roles in neurological function 5. Clinically, HCFC2 mutations may increase susceptibility to infectious diseases 3, and the gene is included in prognostic signatures for lung adenocarcinoma 6 and is recurrently mutated in refractory multiple myeloma 7, indicating involvement in cancer progression and treatment resistance.