Hirayama et al . provide new understanding of the signaling feedback loops that control the mammalian circadian clock. CLOCK and BMAL1 are clock proteins that form a complex and promote clock-controlled transcription of target genes. CLOCK is a histone acetyltransferase that acts to regulate gene expression by initiating remodeling of chromatin. The new work showed that CLOCK acetylated its binding partner BMAL1 when transfected, tagged proteins were expressed in cultured cells or when purified proteins were mixed in vitro. Reconstitution of mouse embryo fibroblasts lacking BMAL1 with a BMAL mutant that lacked the lysine residue acetylated by CLOCK failed to restore circadian gene regulation. Acetylation of BMAL1 appeared to increase association of the CLOCK-BMAL1 complex with cryptochrome 1 (Cry1), which acts as a repressor of CLOCK-BMAL1-induced transcription. Cry1-mediated repression was lacking in cells expressing the acetylation-deficient mutant of BMAL1, and interaction of Cry1 with the CLOCK-BMAL1 complex was lost in a two-hybrid assay with the mutant BMAL1. Acetylation of BMAL1 in vivo also occurs at a time in the circadian cycle when transcription of clock-controlled genes is diminished. Thus, the authors conclude that acetylation of BMAL1 by its binding partner CLOCK contributes to a negative feedback loop that decreases clock-regulated transcription. The positive and negative feedback loops thus appear to be tightly associated because CLOCK’s effect on BMAL contrasts with its role in acetylation of histones, which stimulates transcription of clock-dependent genes. J. Hirayama, S. Sahar, B. Grimaldi, T. Tamaru, K. Takamatsu, Y. Nakahata, P. Sassone-Corsi, CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature , 450 , 1086-1090 (2007). [PubMed]