ARNTL2

Last updated
ARNTL2
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ARNTL2 , BMAL2, CLIF, MOP9, PASD9, bHLHe6, aryl hydrocarbon receptor nuclear translocator like 2
External IDs OMIM: 614517 MGI: 2684845 HomoloGene: 10609 GeneCards: ARNTL2
Orthologs
SpeciesHumanMouse
Entrez

56938

272322

Ensembl

ENSG00000029153

ENSMUSG00000040187

UniProt

Q8WYA1

Q2VPD4

RefSeq (mRNA)

NM_172309
NM_001289679
NM_001289680
NM_001289681

RefSeq (protein)

NP_001234931
NP_001234932
NP_001234933
NP_001234934
NP_064568

NP_001276608
NP_001276609
NP_001276610
NP_758513

Location (UCSC) Chr 12: 27.33 – 27.43 Mb Chr 6: 146.7 – 146.74 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, [5] Bmal2, [6] or Clif, [7] is a gene.

Arntl2 is a paralog to Arntl, which are both homologs of the Drosophila Cycle. [8] Homologs were also isolated in fish, [9] birds [10] and mammals such as mice [11] and humans. [5] Based on phylogenetic analyses, it was proposed that Arntl2 arose from duplication of the Arntl gene early in the vertebrate lineage, followed by rapid divergence of the Arntl gene copy. [11] The protein product of the gene interacts with both CLOCK and NPAS2 to bind to E-box sequences in regulated promoters and activate their transcription. [5] Although Arntl2 is not required for normal function of the mammalian circadian oscillator, it may play an important role in mediating the output of the circadian clock. Perhaps because of this, there is relatively little published literature on the role of Arntl2 in regulation of physiology.

Arntl2 is a candidate gene for human type 1 diabetes. [12]

In overexpression studies, ARNTL2 protein forms a heterodimer with CLOCK to regulate E-box sequences in the Pai-1 promoter. [7] Recent work suggest that this interaction may be in concert with ARNTL/CLOCK heterodimeric complexes. [13]

History

The ARNTL2 gene was originally discovered in 2000 by John B. Hogenesch et al. [5] under the name MOP9 as a part of the PAS domain superfamily of eukaryotic transcription factors and as a homolog to ARNTL/MOP3. Hogenesch’s initial characterization of MOP9 indicated the role of the MOP9 protein as a partner of the bHLH-PAS transcription factor CLOCK in that the MOP9 protein forms a transcriptionally-active heterodimer with the circadian CLOCK protein. The MOP9 protein, like the MOP3 protein, was also found to form heterodimers with MOP4 and hypoxia-inducible factors including HIF1α. The MOP9 gene was found to be coexpressed with CLOCK in the suprachiasmatic nucleus (SCN) in the hypothalamus, the site of the central mammalian circadian oscillator. Due to MOP9 exhibiting extensive sequence identity with genes such as MOP3 and CYCLE, its dimerization with CLOCK, and the brain-specific expression of MOP9, particularly its expression in the SCN, Hogenesch et al. proposed that MOP9 is involved in the regulation of locomotor activity as a part of the mammalian circadian system. Further studies on the MOP9 gene have adopted the names ARNTL2 and BMAL2 in the same style as the previously-discovered ARNTL gene. Like ARNTL/BMAL1, one of the earliest discovered functions of BMAL2 in the circadian system was through its formation of the BMAL2-CLOCK heterodimer, and the relative transactivation of BMAL2-CLOCK and BMAL1-CLOCK have also indicated that BMAL1 and BMAL2 have distinguishable and individually important roles in the circadian system. [14] Knockout studies of BMAL1 and BMAL2 have also demonstrated the regulatory effect of BMAL1 on BMAL2 expression, [15] and have indicated that BMAL2 may play a more significant role in the circadian system than previously appreciated, [16] although the exact nature of the role of BMAL2 has not yet been fully elucidated.

Structure

The BMAL2 protein follows the basic helix-loop-helix structure of the PER-ARNT-SIM family [17] and contains a bHLH-PAS domain in its N-terminal region and a variable C-terminus. [6] The PAS domain acts as a dimerization and binding surface in the aryl hydrocarbon receptor (AHR). Overall, BMAL2 shares much of its structure with BMAL1. [18] However, the location on Chromosome 12 of BMAL2 in humans suggests that the gene may have a different function in the embryo. [17]

Function

BMAL2 forms a heterodimer with CLOCK, and activates transcription, and plays a role in the molecular oscillator. BMAL1 and BMAL2 are positive regulators and activate transcription by binding to proximal (–565 to –560 bp) and distal (–680 to –675 bp) E-box enhancers of the PAI-1 promoter. [13] BMAL 2 functions similarly to BMAL1, but a research study from 2009 found differences in affinities of the homolog genes. [19] The Per2 gene showed a stronger affinity to the BMAL2-CLOCK complex, and CRY2 had a stronger affinity to BMAL1-CLOCK complex. Per2 and CRY2 both inhibit the complexes, and negatively regulate transcription. The true function on Bmal2 is not yet fully understood., A 2010 study by Shi el. al shows that overexpression of BMAL2 in a BMAL1 knockout mice rescues locomotor rhythms and metabolic rhythms. [16] In the same study, rhythmicity was not rescued in peripheral tissues, such as the liver and lung. Bmal2 cannot replace Bmal1, and the two are not interchangeable. The protein does play an active role in the oscillator, but Bmal2 is not required for circadian oscillations in mice.

Interactions

ProteinMechanismSource
PER1/2/3 Transcription of PER1/2/3 is activated by BMAL2-CLOCK heterodimer, and inhibits the activity of said photodimer. [7]
CRY1/2 Transcription of CRY1/2 is activated by BMAL2-CLOCK heterodimer, and inhibits the activity of said photodimer. [7]
DEC1 Transcription of DEC1 is activated by BMAL2-CLOCK heterodimer, suppresses transcription of DEC2, PER2, and DBP. [20]
PAI1 Transcription of PAI1 is activated by BMAL2-CLOCK heterodimer. [13]
SIRT1 Transcription of SIRT1 is activated by BMAL2-CLOCK heterodimer, inhibits CLOCK/NPAS1-BMAL2 activity and promotes the deacetylation and degradation of PER2. [21]

Species distribution

Orthologs for BMAL2 have been found in many mammals other than humans, including chimpanzees, dogs and cows (ARNTL2), mice (Arntl2 and Bmal2), and rats (ARNTL2), [22] as well as in zebrafish. [11] ARNTL2 genes differ significantly more between species than ARNTL genes– BMAL2 proteins have diverged 20 times as quickly as BMAL1 proteins since the genes diverged, suggesting an unidentified function in BMAL1 that does not exist in BMAL2. Human and zebrafish BMAL2 proteins contained only 66% of the same amino acids, rather than 85% between human and zebrafish BMAL1 proteins. [11] Identifying the cause of the comparatively significant differences across species in BMAL2 will be significant for understanding the function of BMAL2 in the circadian clock. [11]

Knockout Studies

Like many genes involved in the circadian system, BMAL2 is a paralog of BMAL1. However, a 2000 study by Bunger et al. [15] demonstrated that unlike other paralog pairs in the circadian system, such as Per1/Per2, Cry1/Cry2, and Clock/Npas2, only a single knockout of either BMAL1 or BMAL2 is required to confer arrhythmicity, rather than a knockout of both paralogs, although other studies have indicated that BMAL1-specific knockouts also have significant effects on metabolism and longevity. [23] [24] The same 2000 study by Bunger et al. also indicated that knockouts of BMAL1 down-regulate expression of BMAL2. [15] A 2010 study by Shi et al. [16] found that BMAL2 expression, conferred by a constitutively expressed promoter, can rescue both circadian rhythmicity in locomotion as well as metabolic phenotypes in Bmal1-knockout mice. Thus, BMAL1 and BMAL2 form a functionally redundant paralog pair, but in mice, BMAL2 expression is regulated by BMAL1 such that knocking out BMAL1 effectively results in the knockout of both BMAL1 and BMAL2, indicating that BMAL2 may play a more important role in the circadian system than previously thought. However, this same study by Shi et al. [16] also found that over-expression of BMAL2 is ultimately insufficient to drive circadian rhythms in the peripheral tissues of mice, thereby suggesting that the behavioral rhythms observed in this study may come from weak molecular clocks fortified through networks with the suprachiasmatic nucleus (SCN). Moreover, a 2015 study conducted by Xu et al. [25] also demonstrated the necessity of the C-terminal region of the BMAL1 protein in the generation of sustained circadian oscillation at the cellular level, identifying two specific domains of the intrinsically unstructured BMAL1 C-terminus that confer this function over BMAL2. The regulation of BMAL1 TAD as a determining mechanism of circadian timing is a topic of ongoing research.

Clinical significance

BMAL1 and BMAL2 genes are known to have a role in glucose homeostasis. [26] A research study from 2015 [26] used forward genetics to find a genotype of  BMAL2 associated with Type 2 diabetes. The BMAL2 rs7958822 is a polymorphism, and has various genotypes: A/G, A/A, and G/G. The study found an association that obese men with BMAL2 rs7958822 A/G and A/C genotypes had a higher prevalence of type 2 diabetes.

Prior research studies have found desynchronization in cortisol synthesis and body temperature in patients with Parkinson’s Disease, suggesting a role of the circadian genes in the disease, [27] The study used RT-PCR assay to track the BMAL2 gene in PD patients, and found changes in expression, specifically at 21:00 and 00:00. More research is needed to find the molecular mechanism behind this, but the results suggest that BMAL 2 and the molecular clock play a role in Parkinson’s disease.

In colorectal cancer cells, the upregulation of BMAL2 has been associated with higher levels of tumor mutational burden (TMB) as a result of subsequent upregulation of PAI1. [28] The relationship between BMAL2 and TMB has been investigated in many models, providing further evidence for a positive correlation between BMAL2 expression and the expression of promoters of TMB. [29] However, there is still a gap in research investigating the predictive capacity of circadian gene expression, including BMAL2, relating to TMB levels.

See also

Related Research Articles

<span class="mw-page-title-main">Suprachiasmatic nucleus</span> Part of the brains hypothalamus

The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is the principle circadian pacemaker in mammals and is necessary for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow the SCN to coordinate the subordinate cellular clocks of the body and entrain to the environment. The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24-hour cycle.

A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">CLOCK</span> Protein-coding gene in the species Homo sapiens

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

An E-box is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG, with a palindromic canonical sequence of CACGTG, is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

<span class="mw-page-title-main">Rev-ErbA alpha</span> Protein-coding gene in the species Homo sapiens

Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of two Rev-Erb proteins in the nuclear receptor (NR) family of intracellular transcription factors. In humans, REV-ERBɑ is encoded by the NR1D1 gene, which is highly conserved across animal species.

<span class="mw-page-title-main">FBXL3</span> Protein-coding gene in the species Homo sapiens

FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3). FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex.

<span class="mw-page-title-main">PER1</span> Protein-coding gene in the species Homo sapiens

The PER1 gene encodes the period circadian protein homolog 1 protein in humans.

<span class="mw-page-title-main">RAR-related orphan receptor gamma</span> Cellular receptor

RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC gene. RORγ is a member of the nuclear receptor family of transcription factors. It is mainly expressed in immune cells and it also regulates circadian rhythms. It may be involved in the progression of certain types of cancer.

<span class="mw-page-title-main">BHLHE41</span> Protein-coding gene in humans

"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3. BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.

<span class="mw-page-title-main">ARNTL</span> Protein-coding gene in the species Homo sapiens

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 ARNTL gene on chromosome 11, region p15.3. It's also known as BMAL1, MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

John B. Hogenesch is an American chronobiologist and Professor of Pediatrics at the Cincinnati Children's Hospital Medical Center. The primary focus of his work has been studying the network of mammalian clock genes from the genomic and computational perspective to further the understanding of circadian behavior. He is currently the Deputy Director of the Center for Chronobiology, an Ohio Eminent Scholar, and Professor of Pediatrics in the Divisions of Perinatal Biology and Immunobiology at the Cincinnati Children's Hospital Medical Center.

Steve A. Kay is a British-born chronobiologist who mainly works in the United States. Dr. Kay has pioneered methods to monitor daily gene expression in real time and characterized circadian gene expression in plants, flies and mammals. In 2014, Steve Kay celebrated 25 years of successful chronobiology research at the Kaylab 25 Symposium, joined by over one hundred researchers with whom he had collaborated with or mentored. Dr. Kay, a member of the National Academy of Sciences, U.S.A., briefly served as president of The Scripps Research Institute. and is currently a professor at the University of Southern California. He also served on the Life Sciences jury for the Infosys Prize in 2011.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

The food-entrainable oscillator (FEO) is a circadian clock that can be entrained by varying the time of food presentation. It was discovered when a rhythm was found in rat activity. This was called food anticipatory activity (FAA), and this is when the wheel-running activity of mice decreases after feeding, and then rapidly increases in the hours leading up to feeding. FAA appears to be present in non-mammals (pigeons/fish), but research heavily focuses on its presence in mammals. This rhythmic activity does not require the suprachiasmatic nucleus (SCN), the central circadian oscillator in mammals, implying the existence of an oscillator, the FEO, outside of the SCN, but the mechanism and location of the FEO is not yet known. There is ongoing research to investigate if the FEO is the only non-light entrainable oscillator in the body.

Charles J. Weitz is a chronobiologist and neurobiologist whose work primarily focuses on studying the molecular biology and genetics of circadian clocks.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040187 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. 1 2 "BMAL2 Gene - GeneCards | BMAL2 Protein | BMAL2 Antibody". www.genecards.org. Retrieved 2023-04-26.
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  13. 1 2 3 Schoenhard JA, Smith LH, Painter CA, Eren M, Johnson CH, Vaughan DE (May 2003). "Regulation of the PAI-1 promoter by circadian clock components: differential activation by BMAL1 and BMAL2". Journal of Molecular and Cellular Cardiology. 35 (5): 473–481. doi:10.1016/S0022-2828(03)00051-8. PMID   12738229.
  14. ↑ Sasaki M, Yoshitane H, Du NH, Okano T, Fukada Y (September 2009). "Preferential inhibition of BMAL2-CLOCK activity by PER2 reemphasizes its negative role and a positive role of BMAL2 in the circadian transcription". The Journal of Biological Chemistry. 284 (37): 25149–25159. doi: 10.1074/jbc.M109.040758 . PMC   2757218 . PMID   19605937.
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  19. ↑ Sasaki M, Yoshitane H, Du NH, Okano T, Fukada Y (September 2009). "Preferential inhibition of BMAL2-CLOCK activity by PER2 reemphasizes its negative role and a positive role of BMAL2 in the circadian transcription". The Journal of Biological Chemistry. 284 (37): 25149–25159. doi: 10.1074/jbc.m109.040758 . PMC   2757218 . PMID   19605937.
  20. ↑ Kawamoto T, Noshiro M, Sato F, Maemura K, Takeda N, Nagai R, et al. (January 2004). "A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation". Biochemical and Biophysical Research Communications. 313 (1): 117–124. doi:10.1016/j.bbrc.2003.11.099. PMID   14672706.
  21. ↑ Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, et al. (July 2008). "SIRT1 regulates circadian clock gene expression through PER2 deacetylation". Cell. 134 (2): 317–328. doi: 10.1016/j.cell.2008.06.050 . PMID   18662546. S2CID   17267748.
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  23. ↑ Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA (November 2004). "BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis". PLOS Biology. 2 (11): e377. doi:10.1371/journal.pbio.0020377. PMC   524471 . PMID   15523558. S2CID   8816869.
  24. ↑ Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP (July 2006). "Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock". Genes & Development. 20 (14): 1868–1873. doi:10.1101/gad.1432206. PMC   1522083 . PMID   16847346. S2CID   13350374.
  25. ↑ Xu, Haiyan; Gustafson, Chelsea L; Sammons, Patrick J; Khan, Sanjoy K; Parsley, Nicole C; Ramanathan, Chidambaram; Lee, Hsiau-Wei; Liu, Andrew C; Partch, Carrie L (June 2015). "Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus". Nature Structural & Molecular Biology. 22 (6): 476–484. doi:10.1038/nsmb.3018. ISSN   1545-9993. PMC   4456216 . PMID   25961797.
  26. 1 2 Yamaguchi M, Uemura H, Arisawa K, Katsuura-Kamano S, Hamajima N, Hishida A, et al. (December 2015). "Association between brain-muscle-ARNT-like protein-2 (BMAL2) gene polymorphism and type 2 diabetes mellitus in obese Japanese individuals: A cross-sectional analysis of the Japan Multi-institutional Collaborative Cohort Study". Diabetes Research and Clinical Practice. 110 (3): 301–308. doi:10.1016/j.diabres.2015.10.009. PMID   26497775.
  27. ↑ Ding H, Liu S, Yuan Y, Lin Q, Chan P, Cai Y (July 2011). "Decreased expression of Bmal2 in patients with Parkinson's disease". Neuroscience Letters. 499 (3): 186–188. doi:10.1016/j.neulet.2011.05.058. PMID   21658431. S2CID   25146780.
  28. ↑ Mazzoccoli, Gianluigi; Pazienza, Valerio; Panza, Anna; Valvano, Maria Rosa; Benegiamo, Giorgia; Vinciguerra, Manlio; Andriulli, Angelo; Piepoli, Ada (March 2012). "ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer". Journal of Cancer Research and Clinical Oncology. 138 (3): 501–511. doi:10.1007/s00432-011-1126-6. ISSN   0171-5216.
  29. ↑ Oishi, Katsutaka; Miyazaki, Koyomi; Uchida, Daisuke; Ohkura, Naoki; Wakabayashi, Miyuki; Doi, Ryosuke; Matsuda, Juzo; Ishida, Norio (April 2009). "PERIOD2 is a circadian negative regulator of PAI-1 gene expression in mice". Journal of Molecular and Cellular Cardiology. 46 (4): 545–552. doi:10.1016/j.yjmcc.2009.01.001. ISSN   0022-2828.
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