ARNTL2
Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9,[5] Bmal2,[6] or Clif,[7] is a gene.
Arntl2 is a
Arntl2 is a candidate gene for human type 1 diabetes.[12]
In overexpression studies, ARNTL2 protein forms a
History
The ARNTL2 gene was originally discovered in 2000 by
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
Protein | Mechanism | Source |
---|---|---|
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
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
- Arntl(Bmal1)
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000029153 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040187 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 10864977.
- ^ a b "BMAL2 Gene - GeneCards | BMAL2 Protein | BMAL2 Antibody". www.genecards.org. Retrieved 2023-04-26.
- ^ PMID 11018023.
- S2CID 18175560.
- PMID 10760301.
- S2CID 45261835.
- ^ S2CID 27706733.
- PMID 16893914.
- ^ PMID 12738229.
- PMID 19605937.
- ^ S2CID 10242426.
- ^ PMID 20153195.
- ^ PMID 12055078.
- S2CID 18752396.
- PMID 19605937.
- PMID 14672706.
- S2CID 17267748.
- S2CID 26619932.
- S2CID 8816869.
- S2CID 13350374.
- PMID 25961797.
- ^ PMID 26497775.
- S2CID 25146780.
- S2CID 8998806.
- PMID 19168071.
External links
- ARNTL2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human ARNTL2 genome location and ARNTL2 gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: Q8WYA1 (Aryl hydrocarbon receptor nuclear translocator-like protein 2) at the PDBe-KB.