ARNTL

4H1040611865n/aENSMUSG00000055116O00327Q9WTL8NM_001297724NM_001243048NM_007489NM_001357070NM_001368412NP_001284653NP_001338733NP_001338734NP_001338735NP_001338736NP_001338737NP_001338738NP_001338739NP_001338740NP_001338741NP_001338742NP_001338743NP_001338744NP_001338745NP_001338746NP_001338747NP_001338748NP_001338749NP_001338750NP_001338751NP_001338752NP_001338753NP_001229977NP_031515NP_001343999NP_001355341Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or Brain and Muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the Bmal1 gene, also known as ARNTL, MOP3, and, less commonly, BHLHE5, BMAL, BMAL1C, JAP3, PASD3, and TIC. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or Brain and Muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the Bmal1 gene, also known as ARNTL, MOP3, and, less commonly, BHLHE5, BMAL, BMAL1C, JAP3, PASD3, and TIC. BMAL1 encodes a transcription factor with a basic helix-loop-helix (bHLH) and two PAS domains. The human Arntl gene has a predicted 24 exons and is located on the p15 band of the 11th chromosome. The BMAL1 protein is 626 amino acids long and plays a key role as one of the positive elements in the mammalian auto-regulatory transcription-translation negative feedback loop (TTFL), which is responsible for generating molecular circadian rhythms. Research has revealed that Bmal1 is the only clock gene without which the circadian clock fails to function in humans. Bmal1 has also been identified as a candidate gene for susceptibility to hypertension, diabetes, and obesity, and mutations in Bmal1 have been linked to infertility, gluconeogenesis and lipogenesis problems, and altered sleep patterns. BMAL1, according to genome-wide profiling, is estimated to target more than 150 sites in the human genome, including all of the clock genes and genes encoding for proteins that regulate metabolism. The Arntl gene was originally discovered in 1997 by two groups of researchers, John B. Hogenesch et al. in March under the name Mop3 and Ikeda and Nomura in April as part of a superfamily of PAS domain transcription factors. In 1998, Hogenesch's additional characterization of MOP3 revealed that its role as the partner of bHLH-PAS transcription factor CLOCK was essential to mammalian circadian clock function. The MOP3 protein, as it was originally known by the Hogenesch group, was found to dimerize with MOP4, CLOCK, and hypoxia-inducible factors. The names BMAL1 and ARNTL were adopted in later papers. One of ARNTL protein's earliest discovered functions in circadian regulation was related to the CLOCK-BMAL1 (CLOCK-ARNTL) heterodimer, which would bind through an E-box enhancer to activate the transcription of the gene encoding vasopressin. However, the gene's importance in circadian rhythms was not fully realized until the knockout of the gene in mice showed complete loss of circadian rhythms in locomotion and other behaviors. SIRT1 regulates PER protein degradation by inhibiting transcriptional activity of the BMAL1:CLOCK heterodimer in a circadian manner through deacetylation. The degradation of PER proteins prevents the formation of the large protein complex, and thus disinhibits the transcriptional activity of the BMAL1:CLOCK heterodimer. The CRY protein is also signaled for degradation by poly-ubiquitination from the FBXL3 protein resulting in the disinhibition of BMAL1:CLOCK heterodimer activity. In addition to the circadian regulatory TTFL loop, Bmal1 transcription is regulated by competitive binding to the retinoic acid-related orphan receptor response element-binding site (RORE) within the promoter of Bmal1. The CLOCK/BMAL1 heterodimer also binds to E-box elements in promoter regions of Rev-Erbα and RORα/ß genes, upregulating transcription and translation of REV-ERB and ROR proteins. REV-ERBα and ROR proteins regulate BMAL1 expression through a secondary feedback loop and compete to bind to Rev-Erb/ROR response elements in the Bmal1 promoter, resulting in BMAL1 expression repressed by REV-ERBα and activated by ROR proteins. Other nuclear receptors of the same families (NR1D2 (Rev-erb-β); NR1F2 (ROR-β); and NR1F3 (ROR-γ)) have also been shown to act on Bmal1 transcriptional activity in a similar manner. Several posttranslational modifications of BMAL1 dictate the timing of the CLOCK/BMAL1 feedback loops. Phosphorylation of BMAL1 targets it for ubiquitination and degradation, as well as deubiquitination and stabilization. Acetylation of BMAL1 recruits CRY1 to suppress the transactivation of CLOCK/BMAL1. The sumoylation of BMAL1 by small ubiquitin-related modifier 3 signals its ubiquitination in the nucleus, leading to transactivation of the CLOCK/BMAL1 heterodimer. CLOCK/BMAL1 transactivation, is activated by phosphorylation by casein kinase 1ε and inhibited by phosphorylation by MAPK. Phosphorylation by CK2α regulates BMAL1 intracellular localization and phosphorylation by GSK3B controls BMAL1 stability and primes it for ubiquitination. In 2004, Rora was discovered to be an activator of Bmal1 transcription within the suprachiasmatic nucleus (SCN), regulated by its core clock. Rora was found to be required for normal Bmal1 expression as well as consolidation of daily locomotor activity. This suggests that the opposing activities of the orphan nuclear receptors RORA and REV-ERBα, the latter of which represses Bmal1 expression, are important in the maintenance of circadian clock function. Currently, Rora is under investigation for its link to autism, which may be a consequence of its function as a circadian regulator. Along with mammals such as humans and mice, orthologs of the Arntl gene are also found in fish (AF144690.1), birds (Arntl), reptiles, amphibians (XI.2098), and Drosophila (Cycle, which encodes a protein lacking the homologous C-terminal domain, but still dimerizes with the CLOCK protein). Unlike mammalian Arntl, circadian regulated, the Drosophila Cycle (gene) is constitutively expressed. In humans, three transcript variants encoding two different isoforms have been found for this gene. The importance of these transcript variants is unknown. The Arntl gene is located within the hypertension susceptibility loci of chromosome 1 in rats. A study of single nucleotide polymorphisms (SNPs) within this loci found two polymorphisms that occurred in the sequence encoding for Arntl and were associated with type II diabetes and hypertension. When translated from a rat model to a human model, this research suggests a causative role of Arntl gene variation in the pathology of type II diabetes. Recent phenotype data also suggest this gene and its partner Clock play a role in the regulation of glucose homeostasis and metabolism, which can lead to hypoinsulinaemia or diabetes when disrupted.