Disease relevance of ARNTL

• With the role of Clock and Bmal1 in fertility becoming clearer, it may be time to pursue the effect of polymorphisms in these genes in relation to the various types of infertility in humans [1].
• The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors [2].
• On the day after the hypothermia, Bmal1 and AVP rhythms showed severely depressed amplitude [3].
• Herpes simplex virus 1 alpha regulatory protein ICP0 functionally interacts with cellular transcription factor BMAL1 [4].
• We have also demonstrated that CLOCK/BMAL1 modulates sensitivity to drug-induced toxicity by controlling B cell responses to active CY metabolites [5].

Psychiatry related information on ARNTL

• Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder [6].

High impact information on ARNTL

• Here, we developed a molecular genetic screen in mammalian cells to identify mutants of the circadian transcriptional activators CLOCK and BMAL1, which were uncoupled from CRYPTOCHROME (CRY)-mediated transcriptional repression [7].
• Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb [8].
• The proteins Clock and Bmal1 form a heterodimer which activates the transcription of the Per gene from the E-box elements in its promoter region [9].
• CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor-binding site, found adjacent to the mouse per1 gene and from an identical E-box known to be important for per gene expression in Drosophila [10].
• Formation of CLOCK/BMAL1 complex following ectopic coexpression of both proteins is followed by their codependent phosphorylation, which is tightly coupled to CLOCK nuclear translocation and degradation [11].

Biological context of ARNTL

• Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively) [6].
• An autofeedback loop associated with transcription of clock gene(s), Per(s), is generally accepted as the molecular machinery of circadian rhythm generation, in which CLOCK/BMAL act as positive regulators and PER/CRY as negative ones [12].
• We have examined the effect of CRYPTOCHROMEs on posttranslational modifications and intracellular distribution of endogenous and ectopically expressed CLOCK(NPAS2) and BMAL1 proteins [13].
• This model provides mechanistic explanation for previously reported dual functional activity of CLOCK/BMAL1 and highlights the involvement of the circadian system in modulating the organism's response to various types of genotoxic stress, including chemotherapy and radiation [13].
• BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system [11].

Anatomical context of ARNTL

• In this study, we indicate the daily expression of clock genes period (Per) 1, 2, 3, Bmal1, and Clock in whole blood cells in 12 healthy male subjects [14].
• Analysis of subcellular localization of CLOCK in embryo fibroblasts of mice carrying different germ-line circadian mutations showed that circadian regulation of nuclear accumulation of CLOCK is BMAL1-dependent [11].
• We find that CRY1 and BMAL1 are phosphoproteins in cultured cells [15].
• The continuous administration of IFN-alpha significantly decreased CLOCK and BMAL1 protein levels in the suprachiasmatic nucleus and liver of mice, thereby preventing oscillations in the expression of clock and clock-controlled output genes [16].
• Treatment of cultured hepatic cells (HepG2) with IFN-alpha significantly decreased the protein levels of CLOCK and BMAL1, which are positive regulators of circadian output rhythm, then their mRNA levels [16].

Associations of ARNTL with chemical compounds

• This binding-dependent coregulation is specific for CLOCK/BMAL1 interaction, as no other PAS domain protein that can form a complex with either CLOCK or BMAL1 was able to induce similar effects [11].
• Interestingly, despite normal melatonin and cortisol secretion patterns, two groups of subjects could be distinguished with significantly different mean PER2 and BMAL1 acrophases [17].
• Bmal-1, Per-2, and the melatonin 1 receptor (MT1) showed a robust oscillatory expression in SCN and adrenal gland, whereas a circadian rhythm of dehydroepiandrosterone sulphate was found in plasma [18].
• These NORs bind to a retinoic acid receptor-related orphan receptor response element (RORE) domain and activate (RORalpha) or repress (REV-ERBalpha) bmal1 expression [19].
• Endogenous EZH2, a polycomb group enzyme that methylates lysine 27 on histone H3, co-immunoprecipitates with CLOCK and BMAL1 throughout the circadian cycle in liver nuclear extracts [20].

Physical interactions of ARNTL

• The active CLOCK/BMAL1 or NPAS2/BMAL1 complexes regulate expression of numerous genes including two Cryptochromes [13].
• Here we report that age alters the 24-h expression profile of Clock and its binding partner Bmal1 in the hamster SCN [21].

Enzymatic interactions of ARNTL

• Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1 [22].

Other interactions of ARNTL

• However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample [6].
• MOP3 was found to associate with the AHR in vitro but not in vivo [23].
• BMAL1 oscillated with approximately the same phase as PER2, instead of being anti-phasic as anticipated from data previously obtained in other peripheral tissues [17].
• The three-dimensional distributions of PER-1, PER-2, CLOCK, and BMAL1 proteins were recorded along colonic crypts by immunofluorescent confocal imaging [24].
• The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon [15].

Analytical, diagnostic and therapeutic context of ARNTL

• Yeast two-hybrid assay detected interactions between Bmal1 and DECs [25].
• The results showed that the expression of Bmal1 was decreased and Cry1 increased significantly after phototherapy [26].
• There was no statistical difference in Bmal1 and Cry1 gene expression and plasma melatonin levels in the control group [26].
• Real-time reverse-transcriptase polymerase chain reaction (RT-PCR) was used to determine the expression of Bmal1 and Cry1 in PBMC, and an enzyme-linked immunosorbent assay was used to determine plasma melatonin levels in 32 breast-milk jaundiced neonates before and after phototherapy, compared with 29 control neonates [26].
• Northern blot analysis indicated that several putative clock genes (bmal1, Clock, and MOP4) are co-expressed in the chicken pineal gland. bmal1 mRNA is expressed in a rhythmic manner in the chicken pineal gland, with peak levels at early subjective night, coincident with the increase in cAANAT expression [27].

References