Circadian and Light-Induced Transcription of Clock Gene Per1 Depends on Histone Acetylation and Deacetylation

Abstract

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...

Selective Boosting of Transcriptional and Behavioral Responses to Drugs of Abuse by Histone Deacetylase Inhibition

“…In this regard, we observed an enhanced upregulation of Per1 in mice that received the sodium butyrate as coadjuvant treatment of repeated morphine injections. Although we did not assess chromatin acetylation at this specific locus, it has been shown that both HDACi (Naruse et al, 2004) and cocaine (Renthal et al, 2009) can induce histone acetylation at the Per1 promoter and increase its transcription. Interestingly, the enhanced expression of Per1 in mice co-treated with sodium butyrate and morphine was associated to increased downregulation of Cry1 and upregulation of Rev-erba (Figure 5c).…”

TheNeurospora crassaWhite Collar-1 dependent Blue Light Response Requires Acetylation of Histone H3 Lysine 14 by NGF-1

“…Evidence for involvement of chromatin modifications in light-inducible transcriptional activation is starting to accumulate (Crosio et al, 2000;Etchegaray et al, 2003;Naruse et al, 2004). Rhythmic acetylation of histone H3 at clock-regulated promoters has been correlated with the circadian activation of clock genes in mammals (Etchegaray et al, 2003;Hastings and Herzog, 2004).…”

The Polycomb Group Protein EZH2 Is Required for Mammalian Circadian Clock Function

“…As histone deacetylase activity is constantly associated with the CLOCK⅐BMAL1 nuclear complex, the balance between acetylation and deacetylation of H3 on circadian promoters appears to be regulated by the rhythmic regulation of histone acetyltransferase activity, with deacetylation predominating during transcriptional repression. Other groups have also reported H3 acetylation rhythms at circadian promoters (17,18).…”

“…As histone deacetylase activity is constantly associated with the CLOCK⅐BMAL1 nuclear complex, the balance between acetylation and deacetylation of H3 on circadian promoters appears to be regulated by the rhythmic regulation of histone acetyltransferase activity, with deacetylation predominating during transcriptional repression. Other groups have also reported H3 acetylation rhythms at circadian promoters (17,18).Our search for other chromatin remodeling activities involved in clockwork function has focused on mechanisms that would link deacetylase activity with other chromatin remodeling events involved in transcriptional inhibition by the mCRY proteins. One such link could be provided by the polycomb group (PcG) 5 proteins, which elicit chromatin-mediated transcriptional repression by both the deacetylation and methylation of H3 (19 -21).…”

“…Changes in chromatin structure due to post-translational modifications of histones are required for transcriptional regulation of gene expression (13,14), and circadian genes are no exception (7,(15)(16)(17)(18). Previously, we showed in the liver clock that the promoter regions of mPer1 and mPer2 undergo rhythmic acetylation of histone H3 that correlates with their transcriptional activation (16).…”