Many co-regulator proteins are recruited by DNA-bound transcription factors to 
remodel chromatin and activate transcription. However, mechanisms for 
coordinating actions of multiple co-regulator proteins are poorly understood. We 
demonstrate that multiple protein-protein interactions by the protein 
acetyltransferase TIP60 are required for estrogen-induced transcription of a 
subset of estrogen receptor alpha (ERα) target genes in human cells. 
Estrogen-induced recruitment of TIP60 requires direct binding of TIP60 to ERα 
and the action of chromatin-remodeling ATPase BRG1, leading to increased 
recruitment of histone methyltransferase MLL1 and increased monomethylation of 
histone H3 at Lys4. TIP60 recruitment also requires preferential binding of the 
TIP60 chromodomain to histone H3 containing monomethylated Lys4, which marks 
active and poised enhancer elements. After recruitment, TIP60 increases 
acetylation of histone H2A at Lys5. Thus, complex cooperation of TIP60 with ERα 
and other chromatin-remodeling enzymes is required for estrogen-induced 
transcription.