![]() ![]() Structural similarities between the WC-1 and PER2 protein suggest that mammalian PER2 may act in a similar way as WC-1 in N. At the same time, it stabilizes the transcriptional factor WC-2 on the promoter of target genes, and target gene expression is promoted 35. After a light pulse, WC-1 changes conformation and directs NGF1 to the chromatin to acetylate histones. The blue light photoreceptor WC-1 interacts in the dark with the histone acetyltransferase NGF1 32, 33 via an LXXLL consensus sequence, a known motif responsible for the interaction between nuclear receptors and their co-activators 34. The WCC consists of a heterodimer formed by the product of the white collar-1 ( wc-1) and white collar-2 ( wc-2) genes 29, 30, 31. The NGF1: White Collar complex (WCC) regulates the light signaling system in this organism. Within the eukaryote domain, the filamentous fungus Neurospora crassa is the most used model system for studying light-inducible pathways, including entrainment and biosynthesis of photoprotective pigments, to name a few 25, 26, 27, 28. Within the wide range of light-responsive genes, the clock gene Per1 and the immediate-early gene cFos are targets of pS133-CREB dependent gene activation 21, 22, 23, 24. The subsequent stabilization of the CREB: CBP complex stimulates the expression of target genes by acetylating nucleosomal histone H3 at lysine 27 (AcH3K27), followed by recruitment of RNA polymerase II 19, 20. Finally, the histone acetyltransferase CREB binding protein (CBP) binds to phospho-Ser133 CREB (pS133-CREB) 18. Subsequently, it translocates into the nucleus, where it interacts via its N-terminal CREB-binding domain (CBD) with CREB 17. Upon stimulation of L-type voltage-gated calcium channels, CRTC1 is dephosphorylated by calcineurin. In neurons, cAMP-regulated transcriptional co-activator 1 (CRTC1) is required for efficient induction of CREB target genes during neuronal activity 15, 16. CREB dimers recognize a specific motif of an 8-base pair palindromic sequence (TGACGTCA) called cAMP response element (CRE) present on regulatory regions of target genes such as Per1 13, 14. This cascade finally promotes phosphorylation of cAMP response element-binding protein (CREB) at serine 133 and 142 10, 11, 12. Light-evoked signals provoke Ca 2+ influx in SCN neurons and activate a phosphorylation cascade, including protein kinase A (PKA), protein kinase G (PKG), Ca 2+/calmodulin-dependent protein kinase (CaMK), and mitogen-activated protein kinases (MAPK) also known as extracellular-signal-regulated kinases (ERK). For instance, in the suprachiasmatic nuclei (SCN) located above the optic chiasm in the ventral part of the hypothalamus, the signal is responsible for the release of neurotransmitters such as glutamate and PACAP 9. Light is perceived by the retina by intrinsically photosensitive retinal ganglion cells (ipRGCs) and transduced via the retinohypothalamic tract (RHT) to many different brain regions. In mammals, light can entrain the circadian clock, regulate mood behaviors, and blood vessel relaxation 6, 7, 8. Light perception is one of the most important mechanisms that provoke biological responses in organisms, from resetting the circadian clock to cell division, metabolism, and redox state regulation 1, 2, 3, 4, 5. Collectively, our data show that PER2 supports the stimulus-dependent induction of the Per1 gene via modulation of the CREB/CRTC1/CBP complex. This process was accompanied by a reduction of histone H3 acetylation and decreased recruitment of RNA Pol II to the Per1 gene. Furthermore, the absence of PER2 abolished the interaction between the histone acetyltransferase CBP and CREB. Using in vitro and in vivo approaches, we show that PER2 modulates the interaction between CREB and its co-regulator CRTC1 to support complex formation only after a light or forskolin stimulus. Here we provide evidence that PER2 acts as a co-factor of CREB to facilitate the formation of a transactivation complex on the CRE element of the Per1 gene regulatory region in response to light or forskolin. However, the details of this pathway are poorly understood. This modification leads CREB to recruit the co-factor CRCT1 and the histone acetyltransferase CBP to stimulate the transcription of genes containing a CRE element in their promoters, such as Period 1 ( Per1). At the molecular level, a stimulus such as light initiates a cascade of kinases that phosphorylate CREB at various sites, including serine 133 (S133). Light affects many physiological processes in mammals such as entrainment of the circadian clock, regulation of mood, and relaxation of blood vessels. ![]()
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