Affinage

NPAS2

Neuronal PAS domain-containing protein 2 · UniProt Q99743

Length
824 aa
Mass
91.8 kDa
Annotated
2026-04-29
79 papers in source corpus 33 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPAS2 is a heme-binding bHLH-PAS transcription factor that functions as a core component of the mammalian circadian clock, with a predominant role in forebrain and peripheral tissues where it operates redundantly with CLOCK. NPAS2 forms an obligate heterodimer with BMAL1 to activate transcription of circadian and tissue-specific target genes (Per1, Per2, Cry1, Dbp, Drd3, CYP1A2, CDC25A, HES1, CX3CL1, Aanat) through E-box elements; its DNA-binding activity is enhanced by reduced NAD(P)H cofactors sensed via the N-terminal bHLH domain and inhibited by carbon monoxide binding to heme coordinated by His119/His171 in the PAS-A domain, while CRY proteins stabilize unphosphorylated NPAS2 and RORα/REV-ERBα regulate Npas2 transcription itself via ROR-response elements (PMID:11441146, PMID:12446832, PMID:22245004, PMID:16628007, PMID:20817722). In the nucleus accumbens, NPAS2 is selectively expressed in D1R-positive medium spiny neurons where it controls dopamine receptor (Drd3) expression, GABAergic signaling (Gabra1), and excitatory synaptic plasticity to regulate cocaine reward sensitivity and anxiety-like behavior (PMID:25444159, PMID:30962277, PMID:29163035). NPAS2-deficient mice exhibit impaired long-term memory, disrupted non-rapid-eye-movement sleep homeostasis, loss of food-entrainable circadian behavior, and attenuated cortical Per2 oscillations, establishing NPAS2 as a critical regulator of sleep, memory, and behavioral rhythmicity (PMID:10864874, PMID:12843397, PMID:16636276).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    NPAS2 was established as a forebrain-enriched bHLH-PAS transcription factor required for long-term memory, revealing that this PAS-domain protein had dedicated neurological functions beyond a predicted role as a generic transcription factor.

    Evidence Targeted lacZ knock-in and behavioral testing (cued and contextual fear conditioning) in Npas2 knockout mice

    PMID:10864874

    Open questions at the time
    • Transcriptional targets mediating the memory phenotype were unknown
    • Whether NPAS2 functioned as a circadian factor in the brain was not addressed
  2. 2001 High

    NPAS2 was shown to heterodimerize with BMAL1 and function as a circadian transcription factor activating Per1, Per2, and Cry1 via E-box elements, with DNA-binding activity modulated by NAD(P)H redox state, linking metabolic sensing to the clock mechanism.

    Evidence In vitro DNA-binding assays with purified proteins and NAD cofactors; conditional induction system in neuroblastoma cells, microarrays, and Northern blotting; Per2 oscillation abolished in Npas2-KO forebrain

    PMID:11441146 PMID:11441147

    Open questions at the time
    • Whether NAD(P)H acted directly on NPAS2 or through an intermediary was unclear
    • The heme-binding properties of NPAS2 had not been characterized
  3. 2001 Medium

    Retinoic acid receptors RARα and RXRα were found to interact with NPAS2 and negatively regulate NPAS2:BMAL1-driven transcription, identifying a non-core-clock input pathway to circadian gene regulation in vascular cells.

    Evidence Co-immunoprecipitation, reporter gene assays, in vivo retinoic acid treatment shifting Per2 rhythms

    PMID:11439184

    Open questions at the time
    • Whether RARα/RXRα regulation of NPAS2 occurs in vivo under physiological retinoid levels was not established
    • The structural basis of the interaction was not defined
  4. 2002 High

    Both PAS-A and PAS-B domains of NPAS2 were shown to bind heme, and carbon monoxide was identified as a gaseous signal that inhibits NPAS2:BMAL1 DNA binding and promotes inactive BMAL1 homodimers, establishing NPAS2 as a heme-based gas sensor.

    Evidence In vitro DNA-binding assays with apo/holo NPAS2 proteins, spectroscopy, and CO gas treatment

    PMID:12446832

    Open questions at the time
    • The axial ligand identity for heme coordination was not resolved
    • Whether CO regulation occurs at physiological intracellular concentrations in vivo was unknown
  5. 2003 High

    NPAS2 was established as functionally important for circadian locomotor behavior and food-entrainable rhythms in vivo, extending its role from a forebrain transcription factor to a bona fide circadian clock component regulating whole-organism behavioral outputs.

    Evidence Locomotor activity monitoring, sleep EEG, and restricted-feeding entrainment assays in Npas2-KO mice

    PMID:12843397

    Open questions at the time
    • The degree of redundancy between NPAS2 and CLOCK in different tissues was not quantified
    • Whether NPAS2 was required in the SCN or only in extra-SCN oscillators was unresolved
  6. 2006 High

    Three advances refined the molecular mechanism: CRY proteins were shown to stabilize unphosphorylated NPAS2 and BMAL1 to repress transcription posttranslationally; NPAS2 was found to regulate NREM sleep homeostasis and cortical Per2 induction in a sex-dependent manner; and the bHLH domain was shown to be required for stable heme binding and E-box DNA recognition.

    Evidence Co-expression, phosphorylation analysis, and reporter assays in cells and Cry-DKO mice; EEG/EMG recording with sleep deprivation in Npas2-KO mice; resonance Raman spectroscopy and QCM DNA-binding assays with domain truncations

    PMID:16628007 PMID:16636276 PMID:16704425

    Open questions at the time
    • How CRY inhibits transcription while preserving DNA binding was mechanistically unclear
    • The identity of the functional heme axial ligands was still debated
  7. 2008 High

    Site-directed mutagenesis of His119 and His171 in PAS-A proved these are the essential heme axial ligands required for BMAL1 heterodimerization and E-box DNA binding, while genetic studies demonstrated NPAS2 and CLOCK are functionally redundant in peripheral circadian transcription.

    Evidence Mutagenesis with Per1-reporter and gel-shift assays in NIH3T3; Clock/Npas2 double-KO mice with FVII rhythmic transcription analysis

    PMID:18230344 PMID:18316400

    Open questions at the time
    • Whether heme occupancy in vivo is limiting or constitutive was unknown
    • The structural basis for NPAS2 vs. CLOCK interchangeability was not defined
  8. 2008 Medium

    NPAS2 knockdown in human cells impaired DNA damage-induced cell cycle arrest and repair capacity, suggesting a role for NPAS2 in genotoxic stress responses beyond circadian timekeeping.

    Evidence RNAi knockdown, comet assay, cell cycle analysis, and PCR expression array in human cells

    PMID:18819933

    Open questions at the time
    • Direct transcriptional targets mediating DNA repair were not identified by ChIP
    • Whether this function requires BMAL1 heterodimerization was not tested
  9. 2010 High

    Npas2 itself was identified as a direct transcriptional target of RORα and REV-ERBα via functional ROR-response elements in its promoter, closing a regulatory loop between the auxiliary and core circadian feedback circuits.

    Evidence ChIP-on-chip, luciferase reporter assays with RORE mutants, RT-PCR; confirmed by RORE mutagenesis and RORα-mutant (sg/sg) fibroblasts

    PMID:20817722 PMID:24196956

    Open questions at the time
    • Whether RORα- and REV-ERBα-mediated regulation of Npas2 is tissue-specific was not fully addressed
  10. 2011 High

    Resonance Raman spectroscopy with systematic mutants resolved the heme coordination mechanism: interdomain interaction between bHLH and PAS-A switches axial ligation from a Cys170/His119 equilibrium to bis-His (His119/His171) coordination, finalizing the structural basis for gas sensing.

    Evidence Resonance Raman spectroscopy of His and Cys mutants of the bHLH-PAS-A domain

    PMID:22245004

    Open questions at the time
    • No crystal structure of the heme-bound bHLH-PAS-A domain exists
    • How CO binding induces the conformational change that disrupts BMAL1 interaction remains structurally unresolved
  11. 2011 Medium

    ChIP in mouse cerebral cortex demonstrated time-of-day-dependent NPAS2:BMAL1 occupancy at Per2, Cry1, Dbp, and Per1 E-boxes in vivo, with sleep deprivation paradoxically decreasing NPAS2 binding at Per2 despite increasing Per2 mRNA, revealing a dissociation between occupancy and transcript output under sleep pressure.

    Evidence Chromatin immunoprecipitation at multiple zeitgeber times in cerebral cortex with and without sleep deprivation

    PMID:22039518

    Open questions at the time
    • The mechanism by which Per2 mRNA increases while NPAS2 binding decreases was not explained
    • Cell-type resolution of cortical ChIP was lacking
  12. 2013 Medium

    The NAD(P)H-sensing domain was mapped to residues 1–61 within the bHLH domain, demonstrating that redox sensing and heme-based gas sensing operate through distinct structural elements of NPAS2.

    Evidence EMSA with systematic truncation mutants of the NPAS2 bHLH domain

    PMID:23831463

    Open questions at the time
    • The molecular identity of the NAD(P)H-binding site within residues 1–61 was not determined
    • Whether this redox sensing operates independently of heme in vivo was not tested
  13. 2014 High

    NPAS2 was shown to be selectively expressed in D1R-positive medium spiny neurons of the nucleus accumbens, where it directly activates Drd3 transcription and regulates cocaine reward; this established NPAS2 as a cell-type-specific circadian regulator of dopaminergic signaling in the reward circuit.

    Evidence AAV-shRNA knockdown in NAc, ChIP-seq identifying Drd3 as direct target, cell sorting qRT-PCR, conditioned place preference

    PMID:25444159

    Open questions at the time
    • Whether NPAS2 regulation of Drd3 involves BMAL1 co-binding at the Drd3 E-box was not shown
    • The full NPAS2 targetome in D1R-MSNs was not defined
  14. 2016 High

    NPAS2 was demonstrated to sustain autonomous circadian rhythms in peripheral cells (fibroblasts) in the absence of CLOCK, resolving the longstanding question of whether NPAS2's redundancy with CLOCK extends beyond the forebrain to peripheral oscillators.

    Evidence Single-cell PER2::LUC bioluminescence imaging in CLOCK-deficient fibroblasts with Npas2 siRNA knockdown

    PMID:26895328

    Open questions at the time
    • Whether NPAS2 drives identical or distinct target gene repertoires compared to CLOCK in peripheral tissues was not resolved
  15. 2017 Medium

    NPAS2 was linked to cell proliferation and tumor biology through direct transcriptional activation of CDC25A (promoting cell cycle progression) and to anxiety-related behavior through transcriptional regulation of GABA-A receptor subunit genes in the ventral striatum.

    Evidence ChIP, Co-IP, reporter assays, and xenograft models for CDC25A in hepatocellular carcinoma; KO and striatal knockdown with behavioral testing for GABA-A targets

    PMID:28333141 PMID:29163035

    Open questions at the time
    • Whether CDC25A regulation by NPAS2 is circadian or constitutive was not determined
    • The specific E-box elements in Gabra genes bound by NPAS2 were not mapped
  16. 2019 High

    Cell-type-specific manipulation demonstrated that NPAS2 in D1R-MSNs (but not D2R-MSNs) controls excitatory synaptic strength and cocaine-induced synaptic potentiation, while tissue-specific studies identified HES1 and HIF-1α as direct NPAS2 targets linking the circadian clock to Notch signaling, fibrogenesis, and metabolic reprogramming.

    Evidence Cre-inducible cell-type-specific shRNA with electrophysiology in D1R vs. D2R MSNs; ChIP and reporter assays for HES1 in hepatic stellate cells and HIF-1α in hepatocellular carcinoma cells with in vivo models

    PMID:30962277 PMID:31765736 PMID:31778954

    Open questions at the time
    • How NPAS2 loss increases excitatory drive in D1R-MSNs at the transcriptional target level was not fully elucidated
    • Whether HIF-1α activation by NPAS2 is E-box-dependent or involves an indirect mechanism was not definitively shown
  17. 2022 High

    NPAS2 was found to physically interact with SIRT1 in the nucleus accumbens, sharing transcriptional targets in reward and metabolic pathways, and to directly activate hepatic CYP1A2 transcription via an E-box-like element, extending the NPAS2 target repertoire to drug metabolism and NAD+-dependent epigenetic regulation.

    Evidence Co-IP and ChIP-seq cross-analysis with behavioral epistasis for SIRT1 interaction; Npas2-KO mice with ChIP-seq, reporter assays, and pharmacokinetic studies for CYP1A2

    PMID:35001440 PMID:36379250

    Open questions at the time
    • Whether SIRT1 deacetylates NPAS2 or BMAL1 in the NPAS2:BMAL1 complex specifically was not tested
    • The full hepatic NPAS2 cistrome remains incompletely defined
  18. 2025 Medium

    Post-transcriptional regulation of Npas2 mRNA by m6A modification was identified: FTO-mediated demethylation destabilizes Npas2 mRNA via PRRC2A, and loss of this suppression elevates NPAS2 to activate HIF-1α-driven glycolysis in macrophages, linking epitranscriptomic regulation of NPAS2 to innate immune metabolic reprogramming.

    Evidence MeRIP-seq, loss/gain-of-function of FTO and NPAS2 in bone marrow-derived macrophages, db/db mouse diabetic nephropathy model

    PMID:39831513

    Open questions at the time
    • Whether m6A regulation of Npas2 mRNA occurs in other cell types or is macrophage-specific was not addressed
    • The specific m6A sites on Npas2 mRNA were not individually validated by site-directed mutagenesis
  19. 2026 Medium

    NPAS2 in medial prefrontal cortex was shown to orchestrate afternoon nap behavior by transcriptionally activating POU2F2, which represses tyrosine hydroxylase to suppress dopamine synthesis in TH+ mPFC neurons, establishing a circadian transcriptional cascade governing daytime sleep architecture.

    Evidence ChIP and reporter assays defining NPAS2→POU2F2→TH pathway, region-specific viral NPAS2 manipulation with in vivo nap monitoring and TH+ neuron electrophysiology

    PMID:41839866

    Open questions at the time
    • Whether the NPAS2→POU2F2→TH axis operates in other dopaminergic brain regions is unknown
    • The contribution of BMAL1 to this mPFC-specific function was not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the crystal or cryo-EM structure of heme-bound NPAS2, alone and in complex with BMAL1 on DNA; (2) the molecular mechanism by which NAD(P)H enhances DNA binding through the bHLH domain; (3) how NPAS2 and CLOCK achieve tissue-specific or target-specific selectivity despite apparent redundancy; and (4) whether the diverse non-circadian functions of NPAS2 (cell cycle, fibrosis, metabolic reprogramming) operate through canonical E-box-dependent BMAL1 heterodimerization or through distinct mechanisms.
  • No high-resolution structure of any NPAS2 domain in complex with BMAL1
  • NAD(P)H-binding site within bHLH residues 1–61 is structurally undefined
  • Tissue-specific NPAS2 vs. CLOCK cistrome comparison is lacking
  • Whether NPAS2 can function independently of BMAL1 in any context is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5 GO:0140299 molecular sensor activity 3
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-9909396 Circadian clock 9 R-HSA-74160 Gene expression (Transcription) 8 R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 3
Partners
ARNTL2BMAL1CRY1CRY2PER2RARARXRASIRT1
Complex memberships
NPAS2:BMAL1 heterodimer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NPAS2 forms an obligate heterodimer with BMAL1, and the DNA-binding activity of the NPAS2:BMAL1 heterodimer is strongly enhanced by reduced NAD cofactors (NADH and NADPH) and inhibited by their oxidized forms in a purified (cell-free) system. In vitro DNA-binding assay with purified proteins and NAD cofactors Science High 11441146
2001 NPAS2:BMAL1 heterodimer functions as a transcriptional activator of Per1, Per2, and Cry1 genes (via E-box elements) and represses BMAL1, establishing NPAS2 as a component of the circadian transcriptional feedback loop operative in the mammalian forebrain. Per2 mRNA oscillation in frontal cortex is abolished in NPAS2-deficient mice. Conditional induction system in neuroblastoma cells, DNA microarrays, Northern blotting, in situ hybridization in NPAS2-knockout mice Science High 11441147
2002 Both PAS-A and PAS-B domains of NPAS2 bind heme as a prosthetic group; heme-loaded (holo) NPAS2:BMAL1 heterodimers bind DNA avidly under reducing conditions, but low micromolar CO inhibits DNA binding of holo-NPAS2 and promotes formation of inactive BMAL1 homodimers at the expense of NPAS2:BMAL1 heterodimers. In vitro DNA-binding assay, spectroscopy, heme-binding biochemistry with apo and holo NPAS2 proteins Science High 12446832
2000 NPAS2 is a bHLH-PAS transcription factor whose expression is spatiotemporally coincident with formation of the frontal association/limbic forebrain pathway; NPAS2-deficient mice exhibit deficits in long-term memory in cued and contextual fear tasks, indicating a dedicated regulatory role in memory acquisition. Targeted lacZ knock-in, behavioral testing (cued and contextual fear conditioning) in knockout mice Science High 10864874
2003 NPAS2 plays a substantive role in maintaining circadian locomotor behaviors under normal light-dark and feeding conditions and is critical for food-entrainment adaptability, as shown by disrupted behavioral rhythms and impaired adaptation to restricted feeding schedules in NPAS2-deficient mice. Locomotor activity monitoring, sleep EEG, restricted food-driven entrainment assays in NPAS2-knockout mice Science High 12843397
2001 Nuclear receptors RARα and RXRα interact with NPAS2 (MOP4) and negatively regulate CLOCK/MOP4:BMAL1-mediated transcriptional activation of clock gene expression in vascular cells; retinoic acid can phase-shift Per2 mRNA rhythmicity in vivo. Co-immunoprecipitation, reporter gene assays, in vivo retinoic acid treatment Cell Medium 11439184
2006 CRY proteins stabilize unphosphorylated forms of CLOCK(NPAS2) and BMAL1 and cause their nuclear accumulation, inhibiting transcriptional activity without disrupting complex formation or DNA binding; this posttranslational regulation is CRY-specific and is confirmed in Cry double-knockout mice. Ectopic co-expression, immunofluorescence, Western blot of phosphorylation states, reporter assays, Cry double-KO mouse tissues Cell cycle Medium 16628007
2006 NPAS2 acts as a transcriptional regulator of non-rapid eye movement sleep homeostasis in a sex-dependent manner; in npas2-/- mice, sleep spindle EEG activity is reduced, delta frequency shifts, and the wake-dependent increase in cortical Per2 expression after sleep deprivation is attenuated, implying NPAS2 drives Per2 transcription in cortex in response to sleep pressure. EEG/EMG recording, sleep deprivation protocol, cortical Per2 mRNA measurement in npas2-/- mice PNAS High 16636276
2006 The heme-bound bHLH-PAS-A domain of NPAS2 exists predominantly as a dimer; the bHLH domain assists stable heme binding (rate constant >100-fold higher than isolated PAS-A alone) and is required for E-box DNA binding in the presence of heme, as shown by quartz-crystal microbalance and spectroscopic analysis. Optical absorption and resonance Raman spectroscopy, heme-binding kinetics, quartz-crystal microbalance DNA-binding assay FEBS Journal High 16704425
2008 Mutation of the heme axial ligands His119 or His171 in the NPAS2 PAS-A domain impairs heterodimer formation with BMAL1 and abolishes DNA binding to the E-box, demonstrating that heme coordination is required for NPAS2 transcriptional activity. Site-directed mutagenesis of full-length NPAS2, reporter gene (Per1 promoter) assay in NIH3T3 cells, gel-shift assay with isolated bHLH-PAS-A domain Biochemical and Biophysical Research Communications High 18230344
2011 Interaction of the PAS-A domain with the bHLH domain of NPAS2 shifts heme axial coordination from a Cys170/His119 equilibrium (isolated PAS-A) to a His119/His171 (bis-His) coordination; His119 and His171 are the functional axial ligands in the bHLH-PAS-A context. Resonance Raman spectroscopy of His and Cys mutants of bHLH-PAS-A domain Journal of Inorganic Biochemistry High 22245004
2008 NPAS2 and CLOCK have overlapping, redundant roles in circadian transcription of Factor VII in the liver; FVII mRNA rhythms are abolished only in Clock-/-;Npas2-/- double-knockout mice but are robust in each single knockout, and both NPAS2:BMAL1 and CLOCK:BMAL1 activate FVII transcription ~4-fold via E-box elements, with this activation suppressed by PER2 and CRY1. Double-knockout mouse genetics, reporter gene assays, E-box mutagenesis, plasma FVII measurement Molecular and Cellular Biology High 18316400
2010 NPAS2 is a direct transcriptional target of RORα and REV-ERBα; both nuclear receptors occupy the NPAS2 promoter at two functional ROR-response elements (ROREs) identified by ChIP/microarray, and both regulate NPAS2 mRNA expression, coordinating the positive arm of the circadian feedback loop. ChIP/microarray (ChIP-on-chip), luciferase reporter assays with RORE mutants, RT-PCR Journal of Biological Chemistry High 20817722
2011 NPAS2 and BMAL1 bind to E-box sequences of Per2, Cry1, Dbp, and Per1 in the mouse cerebral cortex in a time-of-day-dependent manner (peak ~ZT6); sleep deprivation decreases NPAS2:BMAL1 binding to Per2 despite increasing Per2 mRNA, and decreases CLOCK:BMAL1 binding to Dbp consistent with reduced Dbp mRNA. Chromatin immunoprecipitation (ChIP) at multiple zeitgeber times in cerebral cortex, qPCR PLoS ONE Medium 22039518
2016 NPAS2 can compensate for loss of CLOCK in peripheral circadian oscillators (fibroblasts) as well as SCN neurons; knockdown of Npas2 in CLOCK-deficient fibroblasts causes arrhythmicity, demonstrating that NPAS2 sustains autonomous circadian rhythms in peripheral cells. Single-cell bioluminescence imaging of PER2::LUC in CLOCK-deficient fibroblasts with Npas2 siRNA knockdown, luminometry PLoS Genetics High 26895328
2013 NAD(P)H enhances NPAS2:BMAL1 DNA binding specifically; the N-terminal 1–61 residues of NPAS2 (within the bHLH domain) are sufficient to sense NAD(P)H and mediate this enhancement; NAD(P)+ does not inhibit NPAS2 binding under these assay conditions. Electrophoretic mobility shift assay (EMSA) with truncation mutants of NPAS2 bHLH domain and various NAD derivatives Biochemical and Biophysical Research Communications Medium 23831463
2013 Cell-autonomous circadian transcription of the Npas2 gene requires a specific RORE in its upstream promoter and endogenous RORα; dominant-negative RORα, RORα siRNA, and RORα-mutant (sg/sg) mouse embryonic fibroblasts all display damped Npas2 transcriptional oscillations. RORE promoter mutagenesis, dominant-negative and siRNA constructs, RORα-mutant mouse fibroblasts, luciferase reporter Journal of Biological Chemistry High 24196956
2008 RNA interference-mediated knockdown of NPAS2 in human cells impairs cell cycle delay in response to mutagen treatment and reduces DNA repair capacity (comet assay); a PCR expression array shows that NPAS2 knockdown represses several cell cycle and DNA repair genes. RNAi knockdown, comet assay, cell cycle analysis, pathway-based PCR expression array Molecular Cancer Research Medium 18819933
2009 Genome-wide ChIP-on-chip identified 26 genomic loci bound by NPAS2 in MCF-7 cells; 16 were confirmed by qPCR, including cancer-related targets ARHGAP29, CDC25A, CDKN2AIP, CX3CL1, ELF4, GNAL, KDELR1, POU4F2, and THRA. ChIP-on-chip (genome-wide), confirmatory real-time PCR Cancer Letters Medium 19457610
2014 NPAS2 directly transcriptionally activates the Drd3 dopamine receptor gene in the nucleus accumbens (NAc); NPAS2 expression is restricted to Drd1+ neurons in NAc; NPAS2 knockdown in NAc reduces cocaine conditioned place preference and disrupts the diurnal rhythm of Drd3 expression. AAV-shRNA knockdown in NAc, ChIP-seq, conditioned place preference, cell sorting qRT-PCR Biological Psychiatry High 25444159
2010 Both CLOCK and NPAS2 bind the Aanat promoter E-box in chicken photoreceptors (ChIP); NPAS2 knockdown damps the circadian rhythm of Aanat mRNA, while CLOCK knockdown reduces Npas2 expression, demonstrating overlapping roles with CLOCK as the dominant regulator of the photoreceptor clockwork. Gene-specific miRNA knockdown vectors in photoreceptor cell cultures, ChIP, circadian mRNA measurements Journal of Neurochemistry Medium 20345751
2017 NPAS2 heterodimerizes with BMAL1 to bind the E-box element in the CDC25A promoter and transcriptionally upregulates CDC25A phosphatase, which drives CDK2/4/6 dephosphorylation (promoting cell proliferation) and Bcl-2 upregulation (inhibiting apoptosis) in hepatocellular carcinoma cells. Co-immunoprecipitation, ChIP, luciferase reporter assay, overexpression/knockdown with cell cycle and apoptosis readouts, xenograft in vivo Cell Death & Disease Medium 28333141
2017 NPAS2 regulates anxiety-like behavior through transcriptional control of Gabra (GABA-A receptor subunit) genes in the ventral striatum; Npas2 null mutant mice show reduced anxiety and decreased sensitivity to diazepam, and NAc-specific Npas2 knockdown reduces Gabra1 expression. Global Npas2 null mutant behavioral testing (elevated plus maze, light/dark box, open field), AAV-shRNA striatal knockdown, acute/chronic stress Npas2 expression measurement Frontiers in Molecular Neuroscience Medium 29163035
2019 NPAS2 directly transcriptionally activates HIF-1α, which mediates upregulation of glycolytic genes (GLUT1, HK2, GPI, ALDOA, ENO2, PKM2, MCT4) and downregulation of PGC-1α/mitochondrial biogenesis in hepatocellular carcinoma cells, promoting the Warburg effect. Overexpression/knockdown of NPAS2, luciferase reporter assays, ChIP, in vitro and xenograft in vivo metabolic assays Cancer Letters Medium 31765736
2019 NPAS2 directly transcriptionally activates Hes1 (a Notch signaling target) in hepatic stellate cells, promoting liver fibrogenesis; NPAS2 is upregulated in hepatic stellate cells after fibrogenic injury. Luciferase reporter assay, ChIP, NPAS2 overexpression/knockdown in hepatic stellate cells, in vivo fibrosis model Molecular Therapy: Nucleic Acids Medium 31778954
2019 NPAS2 regulates excitatory synaptic transmission specifically in D1R-expressing medium spiny neurons (MSNs) of the nucleus accumbens; cell-type-specific Npas2 knockdown in D1R-MSNs (but not D2R-MSNs) increases excitatory drive, blocks cocaine-induced synaptic potentiation, and reduces cocaine conditioned place preference. Viral-mediated cell-type-specific Npas2 knockdown with Cre-inducible shRNA, electrophysiology (mEPSC), conditioned place preference in Drd1a-tdTomato mice Journal of Neuroscience High 30962277
2021 NPAS2 interacts with CRY2 by co-immunoprecipitation and directly activates the CX3CL1 promoter; overexpression of NPAS2 upregulates CX3CL1, which activates the downstream AKT/mTOR pathway to inhibit autophagy and protect against cardiomyocyte apoptosis from hypoxia/reoxygenation injury. Co-immunoprecipitation, luciferase reporter assay (CX3CL1 promoter), overexpression in cardiomyocytes, in vivo rat I/R model Aging Medium 34460437
2017 ARNTL2/NPAS2 forms a heterodimeric complex that induces PER3 and DBP expression, but is a weaker inducer than the canonical ARNTL/NPAS2 dimer; DEC2 blocks ARNTL2/NPAS2-driven expression; TNF promotes nuclear localization of ARNTL2 and induces ARNTL2 and NPAS2 via NF-κB signaling. Transfection of cloned constructs in HEK293, RT-qPCR, immunofluorescence staining, NF-κB pathway inhibitor (IKK-2 inhibitor IMD-0354) Journal of Circadian Rhythms Medium 30210560
2022 NPAS2 and SIRT1 physically interact (co-immunoprecipitation) in the mouse nucleus accumbens; both show diurnal expression regulated by NAD+; they share transcriptional targets enriched in reward and metabolic pathways (cross-ChIP-seq analysis); NAc-specific Npas2 knockdown or functional Npas2 mutation attenuates SIRT1-mediated increases in cocaine preference. Co-immunoprecipitation, diurnal NAD+ measurement, ChIP-seq cross-analysis, AAV-shRNA NAc knockdown, cocaine conditioned place preference European Journal of Neuroscience Medium 35001440
2022 NPAS2 transcriptionally activates hepatic CYP1A2 by binding to an E-box-like element at −416 bp in the Cyp1a2 promoter; Npas2 knockout mice show decreased CYP1A2 mRNA, protein, and enzymatic activity with loss of diurnal rhythmicity. Npas2-/- knockout mice, luciferase reporter assay, ChIP-seq, in vivo pharmacokinetic (theophylline/phenacetin) assays Biochemical Pharmacology High 36379250
2023 p53 transcriptionally activates NPAS2 in alveolar type II epithelial cells; NPAS2 in turn promotes epithelial-mesenchymal transition (EMT) by transcriptionally upregulating HES1, and NPAS2 overexpression partially rescues the anti-EMT effects of TP53 knockdown. Bleomycin-induced fibrosis mouse model, siRNA knockdown, overexpression, luciferase reporter assay, in vitro EMT assays Cellular Signalling Medium 37406788
2025 In macrophages, FTO (m6A demethylase) reduces m6A modification on Npas2 mRNA through a PRRC2A-dependent mechanism, decreasing Npas2 stability; loss of this suppression leads to elevated NPAS2, which activates HIF-1α signaling to promote glycolysis and M1 macrophage activation in diabetic nephropathy. MeRIP-seq, transcriptome analysis, loss/gain-of-function of FTO and NPAS2 in bone marrow-derived macrophages, db/db mouse model FASEB Journal Medium 39831513
2026 mPFC-expressed NPAS2 orchestrates afternoon nap behavior by circadian suppression of dopamine synthesis: NPAS2 transcriptionally activates the repressor POU2F2, which downregulates tyrosine hydroxylase (TH) expression and dopamine production in TH+ mPFC neurons, reducing their wake-promoting activity during nap hours. In vivo sleep/nap monitoring, ChIP, luciferase reporter assay, viral-mediated region-specific NPAS2 manipulation, TH+ neuron electrophysiology in mice Nature Communications Medium 41839866
2025 NPAS2 transcriptionally represses LPCAT3 expression in vascular smooth muscle cells (VSMCs); loss of NPAS2 elevates LPCAT3 and accumulation of phosphatidylcholines with two polyunsaturated fatty acyl chains (PC-PUFA2S), promoting ferroptosis-induced VSMC phenotypic switching and ascending thoracic aortic aneurysm progression. VSMC-specific Npas2 knockout mice, PDGF-BB treatment, ChIP/reporter assays, lipidomic analysis, ATAA mouse model bioRxivpreprint Low

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science (New York, N.Y.) 772 11441146
2001 NPAS2: an analog of clock operative in the mammalian forebrain. Science (New York, N.Y.) 445 11441147
2001 Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 365 11439184
2002 NPAS2: a gas-responsive transcription factor. Science (New York, N.Y.) 355 12446832
2003 Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science (New York, N.Y.) 308 12843397
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 : official publication of the American College of Neuropsychopharmacology 271 20072116
2007 Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Annals of medicine 203 17457720
2000 Impaired cued and contextual memory in NPAS2-deficient mice. Science (New York, N.Y.) 185 10864874
2006 NPAS2 as a transcriptional regulator of non-rapid eye movement sleep: genotype and sex interactions. Proceedings of the National Academy of Sciences of the United States of America 147 16636276
2007 Association of Per1 and Npas2 with autistic disorder: support for the clock genes/social timing hypothesis. Molecular psychiatry 123 17264841
2010 Characterization of the core mammalian clock component, NPAS2, as a REV-ERBalpha/RORalpha target gene. The Journal of biological chemistry 113 20817722
2009 NPAS2 and PER2 are linked to risk factors of the metabolic syndrome. Journal of circadian rhythms 112 19470168
2011 Sleep loss reduces the DNA-binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex. PloS one 94 22039518
2007 Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk. Breast cancer research and treatment 93 17453337
2007 Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin's lymphoma. International journal of cancer 86 17096334
2016 NPAS2 Compensates for Loss of CLOCK in Peripheral Circadian Oscillators. PLoS genetics 85 26895328
2008 The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response. Molecular cancer research : MCR 85 18819933
2010 ARNTL (BMAL1) and NPAS2 gene variants contribute to fertility and seasonality. PloS one 84 20368993
2014 Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biological psychiatry 72 25444159
2006 Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES. Cell cycle (Georgetown, Tex.) 70 16628007
2008 Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators. Molecular and cellular biology 68 18316400
2019 Circadian clock gene NPAS2 promotes reprogramming of glucose metabolism in hepatocellular carcinoma cells. Cancer letters 66 31765736
2017 NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A. Cell death & disease 57 28333141
2015 Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia. Fertility and sterility 52 25956372
2011 Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. Neuropsychobiology 52 21912186
2015 Association of CLOCK, ARNTL, and NPAS2 gene polymorphisms and seasonal variations in mood and behavior. Chronobiology international 42 26134245
2017 NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors. Frontiers in molecular neuroscience 38 29163035
2013 Common genetic variants in ARNTL and NPAS2 and at chromosome 12p13 are associated with objectively measured sleep traits in the elderly. Sleep 36 23449886
2006 Spectroscopic and DNA-binding characterization of the isolated heme-bound basic helix-loop-helix-PAS-A domain of neuronal PAS protein 2 (NPAS2), a transcription activator protein associated with circadian rhythms. The FEBS journal 35 16704425
2010 CLOCK and NPAS2 have overlapping roles in the circadian oscillation of arylalkylamine N-acetyltransferase mRNA in chicken cone photoreceptors. Journal of neurochemistry 32 20345751
2009 Cancer-related transcriptional targets of the circadian gene NPAS2 identified by genome-wide ChIP-on-chip analysis. Cancer letters 32 19457610
2024 Association between glucose metabolism, the circadian cycle and hypoxia: Evaluation of the NPAS2 and Rev-Erb-α protein serum levels in obstructive sleep apnea patients - a pilot study. Dental and medical problems 31 38804230
2023 NPAS2 promotes aerobic glycolysis and tumor growth in prostate cancer through HIF-1A signaling. BMC cancer 30 36978001
2019 Cell-Type-Specific Regulation of Nucleus Accumbens Synaptic Plasticity and Cocaine Reward Sensitivity by the Circadian Protein, NPAS2. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 30962277
2021 LncRNA Nuclear-Enriched Abundant Transcript 1 Regulates Atrial Fibrosis via the miR-320/NPAS2 Axis in Atrial Fibrillation. Frontiers in pharmacology 27 34040522
2018 Neuronal PAS domain 2 (Npas2) facilitated osseointegration of titanium implant with rough surface through a neuroskeletal mechanism. Biomaterials 27 30428407
2021 Roles of NPAS2 in circadian rhythm and disease. Acta biochimica et biophysica Sinica 26 34415290
2013 Dysregulation of Npas2 leads to altered metabolic pathways in a murine knockout model. Molecular genetics and metabolism 26 24067359
2020 Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration in Npas2 Mutant Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 33268545
2019 Neuronal PAS Domain 2 (Npas2)-Deficient Fibroblasts Accelerate Skin Wound Healing and Dermal Collagen Reconstruction. Anatomical record (Hoboken, N.J. : 2007) 21 30851151
2019 NPAS2 Contributes to Liver Fibrosis by Direct Transcriptional Activation of Hes1 in Hepatic Stellate Cells. Molecular therapy. Nucleic acids 21 31778954
2017 MiR-20a-5p promotes radio-resistance by targeting NPAS2 in nasopharyngeal cancer cells. Oncotarget 21 29285299
2008 Effects of mutations in the heme domain on the transcriptional activity and DNA-binding activity of NPAS2. Biochemical and biophysical research communications 20 18230344
2014 Association between restless legs syndrome and CLOCK and NPAS2 gene polymorphisms in schizophrenia. Chronobiology international 18 24824748
2011 Effects of the bHLH domain on axial coordination of heme in the PAS-A domain of neuronal PAS domain protein 2 (NPAS2): conversion from His119/Cys170 coordination to His119/His171 coordination. Journal of inorganic biochemistry 18 22245004
2009 NPAS2 deletion impairs responses to restricted feeding but not to metabolic challenges. Physiology & behavior 16 20026146
2022 Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing. eLife 15 35040776
2018 NPAS2 regulates proliferation of acute myeloid leukemia cells via CDC25A-mediated cell cycle progression and apoptosis. Journal of cellular biochemistry 14 30536616
2017 DEC2 Blocks the Effect of the ARNTL2/NPAS2 Dimer on the Expression of PER3 and DBP. Journal of circadian rhythms 14 30210560
2022 Involvement of Npas2 and Per2 modifications in zinc-induced acute diurnal toxicity in mice. The Journal of toxicological sciences 13 36450499
2023 Role of the Circadian Gas-Responsive Hemeprotein NPAS2 in Physiology and Pathology. Biology 11 37887064
2022 Sex-specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal and analgesia. Genes, brain, and behavior 11 36053258
2022 Circadian oscillator NPAS2 regulates diurnal expression and activity of CYP1A2 in mouse liver. Biochemical pharmacology 11 36379250
2021 The Circadian Gene NPAS2 Act as a Putative Tumor Stimulative Factor for Uterine Corpus Endometrial Carcinoma. Cancer management and research 11 34992456
2013 Effects of NAD(P)H and its derivatives on the DNA-binding activity of NPAS2, a mammalian circadian transcription factor. Biochemical and biophysical research communications 11 23831463
2025 m6A demethylase Fto inhibited macrophage activation and glycolysis in diabetic nephropathy via m6A/Npas2/Hif-1α axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 10 39831513
2024 NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair. Cell death & disease 10 38291048
2022 Circadian transcription factor NPAS2 and the NAD+ -dependent deacetylase SIRT1 interact in the mouse nucleus accumbens and regulate reward. The European journal of neuroscience 10 35001440
2017 Conditional postnatal deletion of the neonatal murine hepatic circadian gene, Npas2, alters the gut microbiome following restricted feeding. American journal of obstetrics and gynecology 10 28373017
2021 Genetic variants in NPAS2 gene and clinical outcomes of resectable non-small-cell lung cancer. Future oncology (London, England) 9 33541123
2014 Lack of association of the NPAS2 gene Ala394Thr polymorphism (rs2305160:G>A) with risk of chronic lymphocytic leukemia. Asian Pacific journal of cancer prevention : APJCP 9 25227809
2023 Downregulation of a potential therapeutic target NPAS2, regulated by p53, alleviates pulmonary fibrosis by inhibiting epithelial-mesenchymal transition via suppressing HES1. Cellular signalling 8 37406788
2017 A polymorphic GGC repeat in the NPAS2 gene and its association with melanoma. Experimental biology and medicine (Maywood, N.J.) 8 28799406
2015 Hylan G-F 20 attenuates posttraumatic osteoarthritis progression: Association with upregulated expression of the circardian gene NPAS2. Life sciences 8 26388558
2023 Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma. Clinical epigenetics 7 37120564
2021 NPAS2 ameliorates myocardial ischaemia/reperfusion injury in rats via CX3CL1 pathways and regulating autophagy. Aging 7 34460437
2010 A variant affecting miRNAs binding in the circadian gene Neuronal PAS domain protein 2 (NPAS2) is not associated with breast cancer risk. Breast cancer research and treatment 7 21140207
2024 Ellagic Acid Protects against Alcohol-Related Liver Disease by Modulating the Hepatic Circadian Rhythm Signaling through the Gut Microbiota-NPAS2 Axis. Journal of agricultural and food chemistry 6 39495286
2013 Nuclear receptor-mediated cell-autonomous oscillatory expression of the circadian transcription factor, neuronal PAS domain protein 2 (NPAS2). The Journal of biological chemistry 6 24196956
2024 NPAS2, transcriptionally activated by ARRB1, promotes the malignant behaviours of lung adenocarcinoma cells and regulates the reprogramming of glucose metabolism. Clinical and experimental pharmacology & physiology 5 38584327
2015 Current evidence on the relationship between two common polymorphisms in NPAS2 gene and cancer risk. International journal of clinical and experimental medicine 5 26221256
2023 Thyroid-stimulating hormone-thyroid hormone signaling contributes to circadian regulation through repressing clock2/npas2 in zebrafish. Journal of genetics and genomics = Yi chuan xue bao 4 37328030
2017 Prefrontal cortex and dorsomedial hypothalamus mediate food reward-induced effects via npas2 and egr1 expression in rat. Physiological research 3 29355377
2025 NPAS2 Deficiency Leads to Antidepressant-Like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation. Journal of pineal research 1 40820553
2026 Impact of NPAS2 on mPFC dopamine synthesis and nap behavior. Nature communications 0 41839866
2025 Circadian gene NPAS2 modulates pain sensitization in CFA-induced inflammatory pain model. Molecular pain 0 40476504
2025 Circadian Gene NPAS2 Relieves Hypertrophic Scar Formation via CDC25A-Mediated Fibroblasts Activity. Journal of cellular and molecular medicine 0 40548841
2025 NPAS2 gene variants modulate the circadian preference-depression link in Major Depressive Disorder: A mediation role of sleep and somatic symptoms. Chronobiology international 0 41020491
2024 Sex-specific Regulation of Fentanyl Reward by the Circadian Transcription Factor NPAS2. bioRxiv : the preprint server for biology 0 39605449