NPAS2

Last updated
NPAS2
Identifiers
Aliases NPAS2 , MOP4, PASD4, bHLHe9, neuronal PAS domain protein 2
External IDs OMIM: 603347 MGI: 109232 HomoloGene: 1887 GeneCards: NPAS2
Orthologs
SpeciesHumanMouse
Entrez

4862

18143

Ensembl

ENSG00000170485

ENSMUSG00000026077

UniProt

Q99743

P97460

RefSeq (mRNA)

NM_002518

NM_008719

RefSeq (protein)

NP_002509

NP_032745

Location (UCSC) Chr 2: 100.82 – 101 Mb Chr 1: 39.23 – 39.4 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. [7] 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. [8]

Contents

Discovery

The mammalian and mouse Npas2 gene was first sequenced and characterized in 1997 Dr. Steven McKnight's lab and published by Yu-Dong Zhou et al. [9] [10] The gene’s cDNAs encoding mouse and human forms of NPAS2 were isolated and sequenced. RNA blotting assays were used to demonstrate the selective presence of the gene in brain and spinal cord tissues of mice. In situ hybridization indicated that the pattern of Npas2 mRNA distribution in mouse brain is broad and complex, and is largely non-overlapping with that of Npas1. [10]

Using Immunohistochemistry of human testis, Ramasamy et al. (2015) found the presence of NPAS2 protein in both germ cells within the tubules of the testes and in the interstitial space of Leydig cells. [10]

Structure

In humans

The Npas2 gene resides on chromosome 2 at the band q13. [10] The gene is 176,679 bases long and contains 25 exons. [11] The predicted 824-amino acid human NPAS2 protein shares 87% sequence identity with mouse Npas2. [10]

In mice

The Npas2 gene has been found to reside on chromosome 1 at 17.98 centimorgans and is 169,505 bases long. [12]

Function

In the brain

The NPAS2 protein is a member of the basic helix-loop-helix (bHLH)-PAS transcription factor family and is expressed in the SCN. NPAS2 is a PAS domain-containing protein, which binds other proteins via their own protein-protein (PAS) binding domains. Like its paralogue, CLOCK (another PAS domain-containing protein), the NPAS2 protein can dimerize with the BMAL1 protein and engage in a transcription/translation negative feedback loop (TTFL) to activate transcription of the mammalian Per and Cry core clock genes. [8] NPAS2 has been shown to form a heterodimer with BMAL1 in both the brain and in cell lines, suggesting its similarity in function to the CLOCK protein in this TTFL.

Compensation is a key feature of TTFLs that regulate circadian rhythms. BMAL1 compensates for CLOCK in that if CLOCK is absent, BMAL1 will upregulate to maintain the mammalian circadian rhythms. NPAS2 has been shown to be analogous to the function of CLOCK in CLOCK-deficient mice. [8] In Clock knockout mice, NPAS2 is upregulated to keep the rhythms intact. [8] Npas2-mutant mice, which do not express functional NPAS2 protein, still maintain robust circadian rhythms in locomotion. However, like CLOCK-deficient mice in the CLOCK/BMAL1 TTFL, Npas2-mutant mice (in the NPAS2/BMAL1 TTFL) still have small defects in their circadian rhythms such as a shortened circadian period and an altered response to changes in the typical light-dark cycle. [8] In addition, Npas2 knockout mice show sleep disturbances and have decreased expression of mPer2 in their forebrains. [13] Mice without functional alleles of both Clock and Npas2 became arrhythmic once placed in constant darkness, suggesting that both genes have overlapping roles in maintaining circadian rhythms. In both wild-type and Clock knockout mice, Npas2 expression is observed at the same levels, confirming that Npas2 plays a role in maintaining these rhythms in the absence of Clock. [8]

In other tissues

Npas2 is expressed everywhere in the periphery of the body. Special focus has been given to its function in liver tissues, and its mRNA is upregulated in Clock-mutant mice. However, studies have shown that Npas2 alone is unable to maintain circadian rhythms in peripheral tissues in the absence of CLOCK protein, unlike in the SCN. [8] One theory to explain this observation is that neurons in the brain are characterized by intercellular coupling and can thus respond to deficiencies in key clock proteins in nearby neurons to maintain rhythms. In peripheral tissues such as the liver and lung, however, the lack of intercellular coupling does not allow for this compensatory mechanism to occur. A second theory as to why NPAS2 can maintain rhythms in CLOCK-deficient SCNs but not in CLOCK-deficient peripheral tissues, is that there exists an additional unknown factor in the SCN that is not present in peripheral tissues. [8]

Non-circadian function

NPAS2-deficient mice have been shown to have long-term memory deficits, suggesting that the protein may play a key role in the acquisition of such memories. This theory was tested by inserting a reporter gene (lacZ) that resulted in the production of an NPAS2 protein lacking the bHLH domain. These mice were then given several tests, including the cued and contextual fear task, and showed long-term memory deficits in both tasks. [14]

Interactions

NPAS2 has been shown to interact with:

Clinical significance

Npas2 genotypes can be determined through tissue samples from which genomic DNA is extracted and assayed. The assay is performed under PCR conditions and can be used to determine specific mutations and polymorphisms. [19]

Polymorphisms and tumorigenesis

Mounting evidence suggests that the NPAS2 protein and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. [19] These findings provide evidence suggesting a possible role for the circadian Npas2 gene in cancer prognosis. These results have been confirmed in both breast and colorectal cancers. [20]

NPAS2 and mood disorders

Current research has revealed an association between seasonal affective disorder (SAD) and general mood disorder related to NPAS2, ARNTL, and CLOCK polymorphisms. These genes may influence seasonal variations through metabolic factors such as body weight and appetite. [21] [22]

Associated with a connection to mood disorders, NPAS2 has been found to be involved with dopamine degradation. This was first suggested by the observation that the clock components BMAL1 and NPAS2 transcriptionally activated a luciferase reporter driven by the murine monoamine oxidase A (MAOA) promoter in a circadian fashion. [23] This suggested that these two clock components (BMAL1 and NPAS2) directly regulated MAOA transcription. [23] Subsequent findings discovered positive transcriptional regulation of BMAL1/NPAS2 by PER2. In mice lacking PER2, both MAOA mRNA and MAOA protein levels were decreased. Therefore, dopamine degradation was reduced, and dopamine levels in the nucleus accumbens were increased. These findings indicate that degradation of monoamines is regulated by the circadian clock. It is very likely that the described clock-mediated regulation of monoamines is relevant for humans, because single-nucleotide polymorphisms in Per2, Bmal1 , and Npas2 are associated in an additive fashion with seasonal affective disorder or winter depression. [24]

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 principal circadian pacemaker in mammals, responsible for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow it 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, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

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.

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">PER3</span> Protein and coding gene in humans

The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in 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">ARNTL2</span> Protein-coding gene in humans

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

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Human protein and coding gene

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

<span class="mw-page-title-main">PAS domain</span> Protein domain

A Per-Arnt-Sim (PAS) domain is a protein domain found in all kingdoms of life. Generally, the PAS domain acts as a molecular sensor, whereby small molecules and other proteins associate via binding of the PAS domain. Due to this sensing capability, the PAS domain has been shown as the key structural motif involved in protein-protein interactions of the circadian clock, and it is also a common motif found in signaling proteins, where it functions as a signaling sensor.

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.

Steven M. Reppert is an American neuroscientist known for his contributions to the fields of chronobiology and neuroethology. His research has focused primarily on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He was the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School from 2001 to 2017, and from 2001 to 2013 was the founding chair of the Department of Neurobiology. Reppert stepped down as chair in 2014. He is currently distinguished professor emeritus of neurobiology.

<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.

Hitoshi Okamura is a Japanese scientist who specializes in chronobiology. He is currently a professor of Systems Biology at Kyoto University Graduate School of Pharmaceutical Sciences and the Research Director of the Japan Science Technology Institute, CREST. Okamura's research group cloned mammalian Period genes, visualized clock oscillation at the single cell level in the central clock of the SCN, and proposed a time-signal neuronal pathway to the adrenal gland. He received a Medal of Honor with Purple Ribbon in 2007 for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents. His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.

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.

<span class="mw-page-title-main">Sato Honma</span>

Sato Honma is a Japanese chronobiologist who researches the biological mechanisms of circadian rhythms. She mainly collaborates with Ken-Ichi Honma on publications, and both of their primary research focuses are the human circadian clock under temporal isolation and the mammalian suprachiasmatic nucleus (SCN), its components, and associates. Honma is a retired professor at the Hokkaido University School of Medicine in Sapporo, Japan. She received her Ph.D. in physiology from Hokkaido University. She taught physiology at the School of Medicine and then at the Research and Education Center for Brain Science at Hokkaido University. She is currently the director at the Center for Sleep and Circadian Rhythm Disorders at Sapporo Hanazono Hospital and works as a somnologist.

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.

<span class="mw-page-title-main">AVP gene</span> Gene

The arginine vasopressin gene (AVP) is a gene whose product is proteolytically cleaved to produce vasopressin, neurophysin II, and a glycoprotein called copeptin. AVP and other AVP-like peptides are found in mammals, as well as mollusks, arthropods, nematodes, and other invertebrate species. In humans, AVP is present on chromosome 20 and plays a role in homeostatic regulation. The products of AVP have many functions that include vasoconstriction, regulating the balance of water in the body, and regulating responses to stress. Expression of AVP is regulated by the transcription translation feedback loop (TTFL), which is an important part of the circadian system that controls the expression of clock genes. AVP has important implications in the medical field as its products have significant roles throughout body.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000170485 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026077 - 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.
  5. ↑ Zhou YD, Barnard M, Tian H, Li X, Ring HZ, Francke U, Shelton J, Richardson J, Russell DW, McKnight SL (January 1997). "Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system". Proceedings of the National Academy of Sciences of the United States of America. 94 (2): 713–8. Bibcode:1997PNAS...94..713Z. doi: 10.1073/pnas.94.2.713 . PMC   19579 . PMID   9012850.
  6. ↑ Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA (March 1997). "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway". The Journal of Biological Chemistry. 272 (13): 8581–93. doi: 10.1074/jbc.272.13.8581 . PMID   9079689. S2CID   14908247.
  7. ↑ DeBruyne JP, Weaver DR, Reppert SM (May 2007). "CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock". Nature Neuroscience. 10 (5): 543–5. doi:10.1038/nn1884. PMC   2782643 . PMID   17417633.
  8. 1 2 3 4 5 6 7 8 Debruyne JP (December 2008). "Oscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system". Journal of Genetics. 87 (5): 437–46. doi:10.1007/s12041-008-0066-7. PMC   2749070 . PMID   19147932.
  9. ↑ Zhou YD, Barnard M, Tian H, Li X, Ring HZ, Francke U, Shelton J, Richardson J, Russell DW, McKnight SL (January 1997). "Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system". Proceedings of the National Academy of Sciences of the United States of America. 94 (2): 713–8. Bibcode:1997PNAS...94..713Z. doi: 10.1073/pnas.94.2.713 . PMC   19579 . PMID   9012850.
  10. 1 2 3 4 5 "OMIM Entry: 603347 - Neuronal PAS Domain Protein 2 (NPAS2)". OMIM.
  11. ↑ "NPAS2 neuronal PAS domain protein 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-20.
  12. ↑ "Npas2 MGI Mouse Gene Detail - MGI:109232 - neuronal PAS domain protein 2". www.informatics.jax.org. Retrieved 2017-04-20.
  13. ↑ Asher G, Schibler U (November 2006). "A CLOCK-less clock". Trends in Cell Biology. 16 (11): 547–9. doi:10.1016/j.tcb.2006.09.005. PMID   16996737.
  14. ↑ Garcia JA, Zhang D, Estill SJ, Michnoff C, Rutter J, Reick M, Scott K, Diaz-Arrastia R, McKnight SL (June 2000). "Impaired cued and contextual memory in NPAS2-deficient mice". Science. 288 (5474): 2226–30. Bibcode:2000Sci...288.2226G. doi:10.1126/science.288.5474.2226. PMID   10864874.
  15. 1 2 McNamara P, Seo SB, Rudic RD, Sehgal A, Chakravarti D, FitzGerald GA (June 2001). "Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock". Cell. 105 (7): 877–89. doi: 10.1016/S0092-8674(01)00401-9 . PMID   11439184. S2CID   6251321.
  16. ↑ Hogenesch JB, Gu YZ, Jain S, Bradfield CA (May 1998). "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors". Proceedings of the National Academy of Sciences of the United States of America. 95 (10): 5474–9. Bibcode:1998PNAS...95.5474H. doi: 10.1073/pnas.95.10.5474 . PMC   20401 . PMID   9576906.
  17. ↑ Curtis AM, Seo SB, Westgate EJ, Rudic RD, Smyth EM, Chakravarti D, FitzGerald GA, McNamara P (February 2004). "Histone acetyltransferase-dependent chromatin remodeling and the vascular clock". The Journal of Biological Chemistry. 279 (8): 7091–7. doi: 10.1074/jbc.M311973200 . PMID   14645221. S2CID   11865543.
  18. ↑ Lee SM, Zhang Y, Tsuchiya H, Smalling R, Jetten A, Wang L (April 2014). "Circadian clock control of hepatic metabolism via nuclear receptor SHP (579.3)". The FASEB Journal. 28 (1 Supplement): 579.3. doi: 10.1096/fasebj.28.1_supplement.579.3 . S2CID   82270260.
  19. 1 2 Yi C, Mu L, de la Longrais IA, Sochirca O, Arisio R, Yu H, Hoffman AE, Zhu Y, Katsaro D (April 2010). "The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer". Breast Cancer Research and Treatment. 120 (3): 663–9. doi:10.1007/s10549-009-0484-0. PMC   3108061 . PMID   19649706.
  20. ↑ Yuan P, Li J, Zhou F, Huang Q, Zhang J, Guo X, Lyu Z, Zhang H, Xing J (March 2017). "NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A". Cell Death & Disease. 8 (3): e2704. doi:10.1038/cddis.2017.131. PMC   5386534 . PMID   28333141.
  21. ↑ Kim HI, Lee HJ, Cho CH, Kang SG, Yoon HK, Park YM, Lee SH, Moon JH, Song HM, Lee E, Kim L (2015-01-01). "Association of CLOCK, ARNTL, and NPAS2 gene polymorphisms and seasonal variations in mood and behavior". Chronobiology International. 32 (6): 785–91. doi:10.3109/07420528.2015.1049613. PMID   26134245. S2CID   25985873.
  22. ↑ Soria V, Martínez-Amorós E, Escaramís G, Valero J, Pérez-Egea R, García C, Gutiérrez-Zotes A, Puigdemont D, Bayés M, Crespo JM, Martorell L, Vilella E, Labad A, Vallejo J, Pérez V, Menchón JM, Estivill X, Gratacòs M, Urretavizcaya M (May 2010). "Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder". Neuropsychopharmacology. 35 (6): 1279–89. doi:10.1038/npp.2009.230. PMC   3055337 . PMID   20072116.
  23. 1 2 Hampp G, Ripperger JA, Houben T, Schmutz I, Blex C, Perreau-Lenz S, Brunk I, Spanagel R, Ahnert-Hilger G, Meijer JH, Albrecht U (May 2008). "Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood" (PDF). Current Biology. 18 (9): 678–83. Bibcode:2008CBio...18..678H. doi:10.1016/j.cub.2008.04.012. PMID   18439826. S2CID   7006379.
  24. ↑ Partonen T, Treutlein J, Alpman A, Frank J, Johansson C, Depner M, Aron L, Rietschel M, Wellek S, Soronen P, Paunio T, Koch A, Chen P, Lathrop M, Adolfsson R, Persson ML, Kasper S, Schalling M, Peltonen L, Schumann G (March 2007). "Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression". Annals of Medicine. 39 (3): 229–38. doi:10.1080/07853890701278795. PMID   17457720. S2CID   36387074.

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