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FLASH GENE
Symbol ARNTL contributors: mct - updated : 24-05-2015
HGNC name aryl hydrocarbon receptor nuclear translocator-like
HGNC id 701
Location 11p15.2      Physical location : 13.299.324 - 13.408.810
Synonym name
  • bHLH-PAS protein JAP3
  • basic-helix-loop-helix-PAS orphan MOP3
  • member of PAS superfamily 3
  • basic-Helix-Loop-Helix-Per-Arnt-Sim (bHLH-PAS) transcription factor, Brain-Muscle-Arnt-Like-protein 1
  • Synonym symbol(s) TIC, BMAL1, MOP3, JAP3, PASD3, BMAL1c, bHLHe5, MGC47515
    DNA
    TYPE functioning gene
    STRUCTURE 109.49 kb     20 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure 16 exons coding
    MAPPING cloned Y linked N status confirmed
    Physical map
    ADM 11p15.4 adrenomedullin LOC338749 11p15.3 hypothetical LOC338749 AMPD3 11p15 adenosine monophosphate deaminase (isoform E) RNF141 11p15.3 ring finger protein 141 XLKD1 11p15 extracellular link domain containing 1 MRVI1 11p15 murine retrovirus integration site 1 homolog SH2BP1 11pter-p15.4 SH2 domain binding protein 1 (tetratricopeptide repeat containing) EIF4G2 11p15 eukaryotic translation initiation factor 4 gamma, 2 LOC58486 11p15.3 transposon-derived Buster1 transposase-like protein MGC71806 11p15.3 similar to Hypothetical protein LOC233733 USP47 11p15.2 ubiquitin specific protease 47 RIG 11p15.1 ubiquitin specific protease 47 DKK3 11p15.2 dickkopf homolog 3 (Xenopus laevis) MICAL2 11p15.2 dickkopf homolog 3 (Xenopus laevis) FLJ14966 11p15.3 hypothetical protein FLJ14966 PARVA 11p15.2 parvin, alpha TEAD1 11p15.2 TEA domain family member 1 (SV40 transcriptional enhancer factor) LOC119593 11p15.3 similar to RIKEN cDNA 4632411J06 ARNTL 11p15 aryl hydrocarbon receptor nuclear translocator-like GMRP-1 11p15.3-p15.2 K+ channel tetramerization protein PTH 11p15.2-p15.1 parathyroid hormone FLJ22728 11p15.2 hypothetical protein FLJ22728 LOC338750 11p15.2 similar to hypothetical protein FLJ33167 LOC387754 11 LOC387754 SPON1 11p15.2-p14 spondin 1, (f-spondin) extracellular matrix protein RRAS2 11p15.2 related RAS viral (r-ras) oncogene homolog 2 LOC390094 11 similar to ribosomal protein L13a; 60S ribosomal protein L13a; 23 kD highly basic protein COPB 11p15.4-p15.2 coatomer protein complex, subunit beta PSMA1 11p15.1 proteasome (prosome, macropain) subunit, alpha type, 1 PDE3B 11p15.1 phosphodiesterase 3B, cGMP-inhibited MORF4LP3 11p mortality factor 4 like pseudogene 3 CYP2R1 11p15.2 cytochrome P450, family 2, R1 CALCP 11p15.2-p15.1 calcitonin pseudogene CALCA 11p15.2-p15.1 calcitonin/calcitonin-related polypeptide, alpha OR7E41P 11p15 olfactory receptor, family 7, subfamily E, member 41 pseudogene CALCB 11p15.2-p15.1 calcitonin-related polypeptide, beta LOC387755 11 similar to RIKEN cDNA 3830422K02 LOC387756 11 LOC387756 SOX6 11p15.3 SRY (sex determining region Y)-box 6
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    19 splicing 2757 68.76 625 - 1997 9144434
  • a 29 exons variant
  • lacking exons 3 & 6
  • encoding for the same "isoform a" as variant 1
  • 20 splicing 2812 68.76 625 - 1997 9144434
  • a 20 exons variant
  • lacking exon 6
  • encoding for the same "isoform a" as variant 2
  • 20 splicing 2828 64 582 - 1997 9144434
  • a 20 exons variant
  • lacking exon 3
  • encoding for isoform b
  • EXPRESSION
    Rna function photoreceptor
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
     vessel   moderately
    Digestivemouth   highly
    Endocrineneuroendocrinepituitary  moderately
    Lymphoid/Immunespleen   highly
     thymus   highly
    Nervousbrain   highly
    Visualeye   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  moderately
    Muscularstriatumskeletal highly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    not specificadipocyte
    cell lineage
    cell lines
    fluid/secretion blood
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES basic
    STRUCTURE
    motifs/domains
  • a basic helix-loop-helix (HLH) DNA-binding domain
  • an E-R-X-R motif that is highly conserved among basic-helix-loop-helix (bHLH) transcription factors that bind to the E-box transcription element, playing an important role in binding to DNA
  • two PER-ARNT-SIM (PAS) regions
  • a PAS-associated C terminal (PAC) domain
  • extreme C terminus domain playing an essential role in the rhythmic control of E-box-mediated circadian transcription
  • conjugated Other
    mono polymer heteromer , dimer
    HOMOLOGY
    interspecies homolog to rattus Arntl (98.40 pc)
    homolog to murine Arntl (98.40 pc)
    intraspecies homolog to ARNT
    Homologene
    FAMILY
  • PAS superfamily 3
  • basic helix-loop-helix (BHLH) family of transcription factors
  • CATEGORY regulatory , transcription factor , transport carrier
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm,nuclear bodies,PML
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • activating clock and PER1 transcription
  • master regulator of circadian rhythm, also playing important roles in the regulation of adipose differentiation and lipogenesis in mature adipocytes
  • required with CLOCK for both circadian transcription and chromatin modification
  • playing an essential role in the generation of the circadian rhythm
  • may be having a role on the differentiation of pre-B cells to mature B cells
  • critical regulator of CDKN1A expression and hepatocyte proliferation
  • CLOCK/ARNTL regulates CCRN4L (nocturnin) transcription through binding to the E-box of nocturnin promoter
  • with CLOCK, are involved in the neuronal differentiation of adult neural stem/progenitor cells which may extend our understanding of various neurological/psychological disorders linked to adult neurogenesis and circadian rhythm
  • ARNTL2, ARNTL form a circadian paralog pair that is functionally redundant
  • with NPAS2 were associated with reproduction and with seasonal variation
  • CLOCK and ARNTL are critical modulators of molecular, cellular, and functional parameters of skeletal muscle
  • important for the regulation of oxidative stress and DNA damage responses, while deregulation of these processes upon ARNTL deficiency leads to development of stress induced senescence
  • circadian variation in S-phase is controlled by ARNTL intrinsic to keratinocytes, because keratinocyte-specific deletion of ARNTL obliterates time-of-day–dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation
  • regulates the proportion of cells in S-phase in the interfollicular epidermis and upper follicles
  • CLOCK increases NFKB1–mediated transcriptional activation of responsive promoters independent of its circadian partner ARNTL
  • ARNTL and CLOCK contribute to chromatoid body (CB) assembly and physiology
  • is a positive regulator of myogenesis, which may represent a temporal regulatory mechanism to fine-tune myocyte differentiation
  • expression of clock genes in hair follicles is linked to the circadian rhythm and ARNTL can regulate hair growth
  • DNA methylation of the clock genes, in particular, ARNTL is a key player in the disruption of circadian rhythms that are closely associated with various diseases
  • CLOCK and ARNTL drives rhythmic gene expression and regulate biological functions under circadian control
  • ARNTL and Wnt signalling may have a synergistic effect at a particular stage of osteogenesis
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS circadian
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • forming heterodimer with the circadian rythm-associated clock, BMAL1/CLOCK, BMAL1/NPAS2
  • key component of the molecular clock, which controls circadian oscillations
  • ARNTL in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration
  • INTERACTION
    DNA binding to an E-box element (5'-GTGCAC-3')
    RNA
    small molecule cofactor, nucleotide,
  • NAD
  • protein
  • CLOCK
  • PER2 positive regulator of BMAL1 (ARNTL) loop
  • association with the circadian transcriptional repressor cryptochrome 1 (CRY1), depending on the coexistence of CLOCK protein
  • bind in a rhythmic manner to the core enhancer of the MYOD1 promoter
  • DNA-binding of NPAS2 and ARNTL to PER2 was also decreased by sleep deprivation (SD), although SD is known to increase PER2 expression in the cortex (PMId: 22039518)
  • ARNTL and CLOCK may act as Kamikaze activators, in that they are rapidly degraded once bound to DBP chromatin
  • THRAP3 promotes the binding of CLOCK-ARNTL to DNA and links it to the basic transcriptional machinery
  • in mammalian circadian clockwork, the CLOCK-ARNTL complex binds to DNA enhancers of target genes and drives circadian oscillation of transcription
  • HSP90AA1 and HSP90AB1, and not HSP90B1-GRP94 or TRAP1, are responsible for maintaining proper cellular levels of ARNTL protein (r
  • UBE3A could bind to and degrade ARNTL in a ubiquitin ligase-dependent manner
  • PER1 represses the activity of the circadian transcription factors ARNTL and CLOCK, either independently or together with CRYPTOCHROME (CRY)
  • FTO modulates circadian rhythms and inhibits the CLOCK-ARNTL-induced transcription
  • lack of NR1D1 increased ARNTL, NPAS2, CLOCK, and FABP7 expression, confirming the direct regulation of these genes by NR1D1 also in the brain
  • cell & other
    REGULATION
    inhibited by by MAPK1
    during adipose differentiation
    Other positively regulated by CSNK1E, key regulator of matazoan circadian rhythm
    DNA binding activity is regulated by the redox state of NAD (inhibition by oxidized forms)
    phosphorylated by CSNK2A1
    regulated by GSK3B (ARNTL phosphorylation appears to be an important regulatory step in maintaining the robustness of the circadian clock)
    DNA methylation of ARNTL is critical for interfering with circadian rhythms
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    of the clock component ATNTL of beta cells leads to hypoinsulinaemia and diabetes
    tumoral       loss of function
    epigenetic inactivation contributes to the development of hematologic malignancies by disrupting the cellular circadian clock
    Susceptibility to type 2 diabetes and hypertension
    Variant & Polymorphism SNP , other associations between ARNTL SNPs and hypertension or type 2 diabetes
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerlung 
    attractive therapeutic target for malignant pleural mesothelioma
    ANIMAL & CELL MODELS
  • Mop3-/-mice
  • cell structure and function of skeletal muscle is impaired in Clock delta 19 and Bmal1&
  • 8722;/&
    8722; mice
  • Bmal1(-/-) mice develop dilated cardiomyopathy with age, characterized by thinning of the myocardial walls, dilation of the left ventricle, and decreased cardiac performance
  • Deficiency of the circadian clock transcriptional factor Bmal1 results in the development of premature aging in mice
  • loss of Bmal1 in mice leads to reduced total muscle mass and Bmal1-deficient primary myoblasts exhibit significantly impaired myogenic differentiation