ARNTL
Encyclopedia
Aryl hydrocarbon receptor nuclear translocator-like, also known as ARNTL, Bmal1, or Mop3, is a gene
which is associated with susceptibility to hypertension
and type 2 diabetes.
PAS (bHLH-PAS) domain containing protein that forms a heterodimer with a second bHLH-PAS protein, Clock
, or its ortholog, Npas2
. This complex binds to E-box
response element
s in promoter regions of many genes including those encoding the Period (Per1
, Per2
, Per3
) and Cryptochrome (Cry1 and Cry2) proteins. These repressor
proteins are translated, and bind in a complex with casein kinase 1ε (Csnk1e
) and 1δ (Csnk1d
). Next, the entire complex translocates
to the nucleus, where it interacts with the Arntl/Clock heterodimer to inhibit its transactivation
. This hypothesis is supported by the observation that point mutants in the Arntl or Clock render them resistant to interaction and repression by Cryptochromes. Transcription of Period and Cryptochrome genes, therefore, is inhibited, the protein levels of Period and Cryptochrome genes drop, and eventually repression is relieved to allow their transcription to build up again. This process occurs with a period length of approximately 24 hours.
in humans.
nuclear receptors NR1D1
(Rev-erb-α) and NR1F1
(ROR-α) which establishes a second interlocking loop in the mammalian circadian clock
. The other nuclear receptors of the same families (NR1D2
or Rev-erb-β; NR1F2
or ROR-β; NR1F3
or ROR-γ) were also shown to act on Arntl gene.
with HIF1A
, CLOCK
, Aryl hydrocarbon receptor
, SUMO3
, EPAS1
and NPAS2
.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
which is associated with susceptibility to hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and type 2 diabetes.
Function
The protein encoded by this gene is a basic-helix-loop-helixBasic-helix-loop-helix
A basic helix-loop-helix is a protein structural motif that characterizes a family of transcription factors.- Structure :The motif is characterized by two α-helices connected by a loop. In general, transcription factors including this domain are dimeric, each with one helix containing basic amino...
PAS (bHLH-PAS) domain containing protein that forms a heterodimer with a second bHLH-PAS protein, Clock
CLOCK
Clock is a gene encoding a basic-helix-loop-helix-PAS transcription factor that affects both the persistence and period of circadian rhythms...
, or its ortholog, Npas2
NPAS2
Neuronal PAS domain-containing protein 2 is a protein that in humans is encoded by the NPAS2 gene.-Interactions:NPAS2 has been shown to interact with Retinoic acid receptor alpha, EP300, ARNTL and Retinoid X receptor alpha....
. This complex binds to E-box
E-box
An E-box is a DNA sequence which usually lies upstream of a gene in a promoter region. It is a transcription factor binding site where the specific sequence of DNA, CANNTG, is recognized by proteins that can bind to it to help initiate its transcription. Once transcription factors bind to...
response element
Response element
Response elements are short sequences of DNA within a gene promoter region that are able to bind a specific transcription factor and regulate transcription of genes.-Examples:Examples of response elements include:*Hormone response element...
s in promoter regions of many genes including those encoding the Period (Per1
PER1
Period circadian protein homolog 1 is a protein that in humans is encoded by the PER1 gene....
, Per2
PER2
Period circadian protein homolog 2 is a protein that in humans is encoded by the PER2 gene.PER2 contains glucocorticoid response elements and a GRE within the core clock gene Per2 is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo...
, Per3
PER3
Period circadian protein homolog 3 is a protein that in humans is encoded by the PER3 gene....
) and Cryptochrome (Cry1 and Cry2) proteins. These repressor
Repressor
In molecular genetics, a repressor is a DNA-binding protein that regulates the expression of one or more genes by binding to the operator and blocking the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes. This blocking of expression is called...
proteins are translated, and bind in a complex with casein kinase 1ε (Csnk1e
CSNK1E
Casein kinase I isoform epsilon is an enzyme that in humans is encoded by the CSNK1E gene.-Interactions:CSNK1E has been shown to interact with PER1 and AXIN1.-References:...
) and 1δ (Csnk1d
CSNK1D
Casein kinase I isoform delta is an enzyme that in humans is encoded by the CSNK1D gene.-Interactions:CSNK1D has been shown to interact with Gap junction protein, alpha 1.-Further reading:...
). Next, the entire complex translocates
Protein targeting
Protein targeting or protein sorting is the mechanism by which a cell transports proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane, or its exterior via secretion...
to the nucleus, where it interacts with the Arntl/Clock heterodimer to inhibit its transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
. This hypothesis is supported by the observation that point mutants in the Arntl or Clock render them resistant to interaction and repression by Cryptochromes. Transcription of Period and Cryptochrome genes, therefore, is inhibited, the protein levels of Period and Cryptochrome genes drop, and eventually repression is relieved to allow their transcription to build up again. This process occurs with a period length of approximately 24 hours.
Species distribution
In addition to mammals like mice or humans, homologs of the Arntl gene are found in fish, birds and in the fruit fly Drosophila (the fly homolog, cycle, encodes a proteins that lacks a homologous C-terminal domains, but as in mammals it acts as a partner of the CLOCK protein). In humans, three transcript variants encoding two different isoforms have been found for this gene. The importance of these transcript variants is unknown.Knockout studies and clinical significance
Arntl (or Bmal1 or Mop3) is the only component of the mammalian circadian clock whose sole deletion in a mouse model generates arrhythmicity. 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. Recent phenotyping data suggests that this gene and its partner Clock also play a role in regulation of glucose homeostasis and metabolism. Finally, Arntl, Npas2, and Per2 have been associated with seasonal affective disorderSeasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
in humans.
Regulation
Arntl transcription is circadian and reciprocally regulated by the orphanOrphan receptor
An orphan receptor is an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan".-Examples:Examples of orphan...
nuclear receptors NR1D1
Rev-ErbA alpha
Rev-ErbA alpha also known as NR1D1 , is a protein that in humans is encoded by the NR1D1 gene.Rev-erbα is member of the Rev-ErbA family of nuclear receptors and is a transcriptional repressor...
(Rev-erb-α) and NR1F1
RAR-related orphan receptor alpha
RAR-related orphan receptor alpha , also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene.- Function :...
(ROR-α) which establishes a second interlocking loop in the mammalian circadian clock
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
. The other nuclear receptors of the same families (NR1D2
Rev-ErbA beta
Rev-ErbA beta also known as NR1D2 is a protein that in humans is encoded by the NR1D2 gene.Rev-erbβ is a member of the Rev-ErbA family of transcription factors...
or Rev-erb-β; NR1F2
RAR-related orphan receptor beta
RAR-related orphan receptor beta , also known as NR1F2 is a nuclear receptor that in humans is encoded by the RORB gene.- Function :...
or ROR-β; NR1F3
RAR-related orphan receptor gamma
RAR-related orphan receptor gamma is a protein that in humans is encoded by the RORC gene. RORγ is member of the nuclear receptor family of transcription factors.- Gene expression :...
or ROR-γ) were also shown to act on Arntl gene.
Interactions
ARNTL has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with HIF1A
HIF1A
Hypoxia-inducible factor 1, alpha subunit , also known as HIF1A, is a protein that in humans is encoded by the HIF1A gene...
, CLOCK
CLOCK
Clock is a gene encoding a basic-helix-loop-helix-PAS transcription factor that affects both the persistence and period of circadian rhythms...
, Aryl hydrocarbon receptor
Aryl hydrocarbon receptor
The Aryl hydrocarbon receptor is a member of the family of basic-helix-loop-helix transcription factors. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones...
, SUMO3
SUMO3
Small ubiquitin-related modifier 3 is a protein that in humans is encoded by the SUMO3 gene.-Interactions:SUMO3 has been shown to interact with ARNTL and Thymine-DNA glycosylase.-Further reading:...
, EPAS1
EPAS1
Endothelial PAS domain-containing protein 1 is a protein that in humans is encoded by the EPAS1 gene.- Function :This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall...
and NPAS2
NPAS2
Neuronal PAS domain-containing protein 2 is a protein that in humans is encoded by the NPAS2 gene.-Interactions:NPAS2 has been shown to interact with Retinoic acid receptor alpha, EP300, ARNTL and Retinoid X receptor alpha....
.