a transcriptional repressor and core component of the circadian clock. A member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Behaves as a negative element in the circadian transcriptional loop. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the circadian feedback loop, and form heterodimers that activate the transcription of core clock genes and clock-controlled genes. The core clock genes PER1/2/3 and CRY1/2 are transcriptional repressors forming the negative limb of this feedback loop. They interact with and inhibit the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimers, negatively regulating their own expression. The PER complex appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK-ARTNL/BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-ARTNL/BMAL1 interactions. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. Widely expressed. Found in heart, brain, placenta, lung, liver, skeleatal muscle, kidney and pancreas. High levels in skeletal muscle and pancreas. Low levels in lung. Isoform 2 is expressed in keratinocytes (at protein level). 2 alternatively spliced human isoforms have been reported. Note: This description may include information from UniProtKB.
Protein type: Nuclear receptor co-regulator; Nucleolus; Transcription factor
Cellular Component: nucleolus; nucleus; perinuclear region of cytoplasm
Molecular Function: protein binding; transcription coactivator activity; transcription regulatory region sequence-specific DNA binding
Biological Process: circadian regulation of gene expression; circadian regulation of translation; circadian rhythm; fatty acid metabolic process; gluconeogenesis; glycogen biosynthetic process; histone H3 deacetylation; lactate biosynthetic process; negative regulation of circadian rhythm; negative regulation of fat cell proliferation; negative regulation of protein ubiquitination; negative regulation of transcription by RNA polymerase II; negative regulation of transcription regulatory region DNA binding; negative regulation of transcription, DNA-templated; positive regulation of cold-induced thermogenesis; positive regulation of nucleic acid-templated transcription; regulation of cell cycle; regulation of circadian rhythm; regulation of glutamate uptake involved in transmission of nerve impulse; regulation of insulin secretion; regulation of neurogenesis; regulation of vasoconstriction; response to ischemia; white fat cell differentiation