Basic helix-loop-helix ARNT-like protein 1

The BMAL1 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. The MOP3 protein, as it was originally known by the Hogenesch group, was found to dimerize with MOP4, CLOCK, and hypoxia-inducible factors. 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. == Genetics ==

Regulation of Bmal1 activity 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. 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. Species distribution 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. 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. Furthermore, BMAL1 has been shown to influence excitability and seizure threshold. In addition, BMAL1 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. An SNP in Bmal1 was identified as having a link with bipolar disorder. Arntl, Npas2, and Per2 have also been associated with seasonal affective disorder in humans. Alzheimer's patients have different rhythms in BMAL1 methylation suggesting that its misregulation contributes to cognitive deficits. Research has also shown that BMAL1 and other clock genes drive the expression of clock-controlled genes that are associated with Autism Spectrum Disorder (ASD). Lastly, BMAL1 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. In animal models of multiple sclerosis (MS), namely the experimental autoimmune encephalomyelitis (EAE) model, it has been shown that daily circadian rhythms can play an important role in disease pathology. Inducing EAE through the active immunization of mice with myelin oligodendrocyte glycoprotein (MOG) peptide during the rest phase is more efficient in comparison to that during the active phase. Disparity in EAE induction is critically dependent on BMAL1 expression in T cells and myeloid cells. T cell or myeloid-specific deletion of Bmal1 has been shown to cause more severe pathology and is sufficient to abolish the rest vs. active induction effect. == Structure ==

The BMAL1 protein contains fours domains according to its crystallographic structure: a basic helix-loop-helix (bHLH) domain, two PAS domains called PAS-A and PAS-B, and a trans-activating domain. The dimerization of CLOCK:BMAL1 proteins involves strong interactions between the bHLH, PAS A, and PAS B domains of both CLOCK and BMAL1 and forms an asymmetrical heterodimer with three distinct protein interfaces. The PAS-A interactions between CLOCK and BMAL1 involves an interaction, in which an α-helix of CLOCK PAS-A and the β-sheet of BMAL1 PAS-A, and an α-helix motif of the BMAL1 PAS-A domain and the β-sheet of CLOCK PAS-A. CLOCK and BMAL1 PAS-B domains stack in a parallel fashion, resulting in the concealment of different hydrophobic residues on the β-sheet of BMAL1 PAS-B and the helical surface of CLOCK PAS-B, such as Tyr 310 and Phe 423. == Function ==

Circadian clock The protein encoded by the BMAL1 gene in mammals binds with a second bHLH-PAS protein via the PAS domain, CLOCK (or its paralog, NPAS2) to form a heterodimer in the nucleus. in the promoter regions of Per (Per1 and Per2) and Cry genes (Cry1 and Cry2). This inhibits the heterodimer activation of the transcription of Per and Cry genes, and causes protein levels of PER and CRY drop. This transcription-translation negative feedback loop (TTFL) is modulated in the cytoplasm by phosphorylation of PER proteins by casein kinase 1ε or δ (CK1 ε or CK1 δ), targeting these proteins for degradation by the 26S proteasome. The TTFL loop of nocturnal mice 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 and supports the notion that this molecular mechanism is rhythmic. Pregnancy Basic helix-loop-helix ARNT-like protein 1, or more commonly known as Bmal1, encodes for a transcriptional factor that when it heterodimerizes with Clock and Npas2 proteins, regulates gene expression for circadian rhythms via E-box elements. It dictates the timing of different physiological process by synchronizing them to environmental cues. The center of this orchestration is most notably, in mammals, the suprachiasmatic nucleus (SCN). metabolic disorders, immune dysfunction and tumorigenesis. Bmal1's regulation in circadian rhythms influences reproductive physiology such as ovulation, fertilization, and embryonic and fetal development via maternal circadian communication. Studies have suggested mice that lack Bmal1 display reproductive ineffectiveness such as irregular cycles and reduced fertility. Shift work and chronic jet lag have been suggested to correlate with outcomes such as preterm labor, low birth weight, and gestational diabetes. Gene knockout models in mice have helped to understand the role Bmal1 has in transcriptional translational feedback loops and the effects of its absence on circadian rhythms and other physiological processes. These knockout models have helped in revealing new insights into individualistic healthcare and disease prevention. == Knockout studies==

The Arntl gene is an essential component within the mammalian clock gene regulatory network. It is a point of sensitivity within the network, as it is the only gene whose single knockout in a mouse model generates arrhythmicity at both the molecular and behavioral levels. are small in stature, age quickly, and have progressive arthropathy that results in having less overall locomotor activity than wild type mice. However, recent research suggests that there might be some redundancy in the circadian function of Arntl with its paralog Bmal2. BMAL1 KO is not embryonically lethal and mice with BMAL1 ablated in adulthood do not express the symptoms of BMAL1 KO mice. A recent study finds that BMAL1 KO mice exhibit autistic-like behavioral changes, including impaired sociability, excessive stereotyped and repetitive behaviors, and motor learning disabilities. These changes are associated with hyperactivation of the mTOR signaling pathway in the brain and can be ameliorated by an antidiabetic drug metformin. BMAL1 binding is regulated in a tissue-specific manner by numerous factors including non-circadian ones. Following, tissue-specific KOs cause unique effects. BMAL1 has been shown to be important in bone metabolism as osteoblast BMAL1 KO mice have lower bone mass than their wild type counterparts. It is also important for energy metabolism as BMAL1 modulates the regulation of hepatic metabolites, the secretion of insulin and proliferation of pancreatic islets, adipocyte differentiation and lipogenesis, and skeletal muscle glucose metabolism. Curiously, global KO of BMAL1 has no effect on food anticipatory activity (FAA) in mice but in BMAL1 deletions in certain regions in the hypothalamus outside the SCN eliminate FAA. Knockout studies have demonstrated that BMAL1 is a key mediator between the circadian clock and the immune system response. By loss of Ccl2 regulation, BMAL1 KO in myeloid cells results in hindered monocyte recruitment, pathogen clearance, and anti-inflammatory response (consistent with the arthropathy phenotype). Immune cells such as TNF-α and IL-1β reciprocally repress BMAL1 activity. BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. == Interactions ==

Arntl has been shown to interact with: • Aryl hydrocarbon receptor • CREBBP • CRY1 • NPAS2 == See also ==