|Aryl hydrocarbon receptor nuclear translocator-like|
|Symbols||; BMAL1; BMAL1c; JAP3; MOP3; PASD3; TIC; bHLHe5|
|RNA expression pattern|
Aryl hydrocarbon receptor nuclear translocator-like, also known as Arntl, Bmal1, or Mop3, is a gene that encodes for a basic helix-loop-helix-PAS domain (bHLH-PAS domain) transcription factor. In the human, it is 110,615 bases long and located on the p15 band of the 11th chromosome. This protein plays a key role as one of the positive elements in the mammalian autoregulatory transcription translation negative feedback loop (TTFL), which is responsible for generating molecular circadian rhythms. Arntl has also been identified as a candidate gene for susceptibility to hypertension and Type II diabetes.
Function and regulation
The Arntl gene was originally discovered in 1997 by two groups of researches, Hogenesch and Bradfield in March  and Ikeda and Nomura in April  as part of a superfamily of bHLH-PAS domain transcription factors. The ARNTL protein, also known as MOP3, 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 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 knock-out of the gene in mice showed complete loss of circadian rhythms in locomotion and other behaviors. Thus, ARNTL is the only clock gene that by itself is necessary for circadian rhythm generation.
The protein encoded by the Arntl gene forms a heterodimer with a second bHLH-PAS protein, CLOCK, or a paralog, NPAS2. This complex binds to E-box response elements in promoter regions of many genes including those encoding the Period (PER1, PER2, PER3) and Cryptochrome (CRY1 and CRY2) proteins. CLOCK/BMAL1 heterodimers also activate transcription of the orphan nuclear receptor gene Rev-Erb, where the REV-ERB protein it encodes for represses Bmal1 transcription by binding to Rev-Erb/ROR response elements in the Bmal1 promoter.
As PER and CRY proteins are translated, these repressor proteins bind in a repressor complex with casein kinase 1ε (CSNK1E) and 1δ (CSNK1D). This process can be modulated in the cytoplasm by the degradation of PER protein through its phosphorylation by casein kinase 1ε (CSNK1E) and 1δ (CSNK1D). Next, the repressor complex translocates to the nucleus, where it interacts with the CLOCK/BMAL1 heterodimer to inhibit its transactivation. This hypothesis is supported by the observation that point mutations in the Arntl and Clock genes render them resistant to interaction and repression by Cryptochromes. Transcription of Per and Cry genes, therefore, is inhibited and the protein levels of PER and CRY drop. The repressor complex also inhibits Rev-Erb transcription resulting in an activation of Bmal1 transcription. When such repression is eventually relieved by a drop in the protein levels of PER and CRY, a high level of BMAL1 allows transcription of the Per and Cry genes to begin again.
Several posttranslational modifications of BMAL1 have been shown to be important for the proper timing and activation of the CLOCK/BMAL1 complex. Acetylation of BMAL1 facilitates the recruitment of CRY1 to the CLOCK/BMAL1 complex and represses the complex's transactivation . The sumoylation of BMAL1 by small ubiquitin-related modifier 3 signals its ubiquitination in the nucleus which leads to the transactivation of the CLOCK/BMAL1 heterodimer and its protein turnover. In addition, phosphorylation of BMAL1 by multiple kinases has been reported through the functional interactions between phosphorylation and other posttranslational regulators. Phosphorylation by casein kinase 1ε activates CLOCK/BMAL1 transactivation, while phosphorylation by MAPK inhibits it. Phosphorylation by CK2α regulates BMAL1 intracellular localization  and phosphorylation by GSK3B controls BMAL1 stability and primes it for ubiquitination.
It has also been observed in the negative feedback loop of nocturnal mice, that transcription levels of the Bmal1 gene peak at CT18, during the mid-subjective night, anti-phase to the transcription levels of Per, Cry, and other clock control genes, which peak at CT6, during the mid-subjective day. This process occurs with a period length of approximately 24 hours.
In addition to the circadian regulatory transcriptional translational negative feedback loop (TTFL) described above, Arntl gene transcription is reciprocally regulated by the orphan nuclear receptors NR1D1 (Rev-erb-α) and NR1F1 (ROR-α), which establish a second interlocking loop in the mammalian circadian clock. This loop is induced when CLOCK-BMAL1 heterodimers activate the transcription of Rev-ErbA and Rora, two retinoic acid-related orphan nuclear receptors. REV-ERBa and RORa subsequently compete to bind retinoic acid-related orphan receptor response elements (ROREs) present in the Arntl promoter. Through the subsequent binding of ROREs, members of ROR and REV-ERB are able to regulate Arntl. While RORs activate the transcription of Arntl, REV-ERBs repress this transcription. Hence, the circadian oscillation of Arntl is both positively and negatively regulated by RORs and REV-ERBs. 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 the Arntl gene.
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. In regards to other functions, another study shows that the CLOCK/BMAL1 complex upregulates human LDLR promoter activity, suggesting the Arntl gene also plays a role in cholesterol homeostasis. In addition, Arntl gene expression, along with that of other core clock genes, were discovered to be lower in patients with bipolar disorder, suggesting a problem with circadian function in these patients. Arntl, Npas2, and Per2 have also been associated with seasonal affective disorder in humans. Lastly, Arntl has been identified through functional genetic screening as a putative regulator of the p53 tumor suppressor pathway suggesting potential involvement in the circadian rhythms exhibited by cancer cells.
The Arntl gene is an essential and nonredundant component within the mammalian clock gene regulatory network, since it is the only gene within the mammalian circadian clock whose sole deletion in a mouse model generates arrhythmicity at both the molecular and behavioral levels. However, recent research suggests that there might be some redundancy in the circadian function of Arntl with its paralog Bmal2. In addition to defects in the clock, these Arntl null-mice also have reproductive problems, are small in stature, age quickly, and have progressive arthropathy that results in having less overall locomotor activity than wild type mice.
In addition to mammals like mice and humans, homologs of the Arntl gene are 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 the mammalian Artnl, however, the drosophila Cycle (gene) is constitutively expressed instead of circadian regulated. In humans, three transcript variants encoding two different isoforms have been found for this gene. The importance of these transcript variants is unknown.
Arntl has been shown to interact with:
- Arntl2 - Arntl2 (Bmal2) is a paralog of Arntl (Bmal1) that encodes for a basic helix-loop-helix PAS domain transcription factor. It, too, has been shown to play a circadian role, with its protein BMAL2 forming a transcriptionally active heterodimer with the CLOCK protein. It may also play a role in hypoxia.
- Cycle - Cycle is the Drosophila melanogaster ortholog of Arntl.
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