The classical view of the molecular clock is based on interlocked 
transcriptional-translational feedback loops. Because a substantial fraction of 
the mammalian genome is expressed in a circadian manner, chromatin remodeling 
has been proposed to be crucial in clock function. Here we show that Lys4 (K4) 
trimethylation of histone H3 is rhythmic and follows the same profile as 
previously described H3 acetylation on circadian promoters. MLL1, a mammalian 
homolog of Drosophila trithorax, is an H3K4-specific methyltransferase 
implicated in transcriptional control. We demonstrate that MLL1 is essential for 
circadian transcription and cyclic H3K4 trimethylation. MLL1 is in a complex 
with CLOCK-BMAL1 and contributes to its rhythmic recruitment to circadian 
promoters and to H3 acetylation. Yet MLL1 fails to interact with CLOCKΔ19, 
providing an explanation for this mutation's dominant negative phenotype. Our 
results favor a scenario in which H3K4 trimethylation by MLL1 is required to 
establish a permissive chromatin state for circadian transcription.