Circadian clock genes are regulated through a transcriptional-translational feedback loop. Alterations of the chromatin structure by histone acetyltransferases and histone deacetylases (HDACs) are commonly implicated in the regulation of gene transcription. However, little is known about the transcriptional regulation of mammalian clock genes by chromatin modification. Here, we show that the state of acetylated histones fluctuated in parallel with the rhythm of mouse Per1 (mPer1) or mPer2 expression in fibroblast cells and liver. Mouse CRY1 (mCRY1) repressed transcription with HDACs and mSin3B, which was relieved by the HDAC inhibitor trichostatin A (TSA). In turn, TSA induced endogenous mPer1 expression as well as the acetylation of histones H3 and H4, which interacted with the mPer1 promoter region in fibroblast cells. Moreover, a light pulse stimulated rapid histone acetylation associated with the promoters of mPer1 or mPer2 in the suprachiasmatic nucleus (SCN) and the binding of phospho-CREB in the CRE of mPer1. We also showed that TSA administration into the lateral ventricle induced mPer1 and mPer2 expression in the SCN. Taken together, these data indicate that the rhythmic transcription and light induction of clock genes are regulated by histone acetylation and deacetylation.Most organisms have physiological and behavioral rhythms, so-called circadian rhythms, having an intrinsic period of approximately 24 h. The circadian clock is an endogenous oscillator that controls daily physiological and behavioral rhythms. In mammals, molecular oscillators exist in the suprachiasmatic nucleus (SCN) of the brain, a master clock (19,21,31), and also in peripheral tissues (24,48). Even in fibroblast cell lines, clock genes are induced rhythmically under certain conditions (1, 5, 47). The core circadian system consists of an interacting transcriptional-translational feedback loop of clock genes in an individual cell (11, 31). A negative feedback loop involves the regulation of two period genes (Per1 and -2) and two cryptochrome genes (Cry1 and -2) (22, 33). The rhythmic transcription is driven by the basic helix-loop-helix-PAS protein (CLOCK-BMAL1) complex, which binds the E-box on the mPer1 and mPer2 genes (14). This CLOCK-BMAL1-mediated transcription is, in turn, repressed by the translated products of clock genes, such as the mPER and mCRY protein complex, which translocate to the nucleus (14,17,22,33).On the other hand, rapid inductions of mPer1 and mPer2 are also involved in phase resetting of the circadian rhythm (3,4,34). A light pulse during subjective night induced rapid increases in mPer1 and mPer2 expression in the SCN and caused a behavioral phase shift. Thus, mPer1 and mPer2 are considered to work both in the generation of circadian rhythm and in light entrainment.It has recently become clear that histone modification plays an important role when genes are transcribed in the nucleus and basic domains in the histone N-terminal are modified, such as by phosphorylation, acetylation, methylation, or ubiquityla...
