The gene encoding hepatocyte nuclear factor 4K K (HNF4K K) possesses two alternative promoters responsible for developmental and tissue-speci¢c expression of HNF4K K1 and HNF4K K7. The two isoforms possess di¡erent N-termini and exhibit distinct transactivation properties. We show here for the ¢rst time that the e¡ects mediated by HNF4K K isoforms in concert with three di¡erent coregulators result in promoter-speci¢c responses. Transcript levels of silencing mediator for retinoid and thyroid receptors and glucocorticoid receptor interacting protein-1 in the liver are reduced at birth, a time point when many genes are strongly activated, suggesting that the e¡ects of coregulators on HNF4K K activity in vivo could be determined by the levels of their expression as well as by the target promoter.