Affinage

NPAS2

Neuronal PAS domain-containing protein 2 · UniProt Q99743

Length
824 aa
Mass
91.8 kDa
Annotated
2026-06-10
80 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPAS2 is a bHLH-PAS transcription factor that forms an obligate heterodimer with BMAL1 to bind E-box DNA elements and drive the positive arm of the circadian transcriptional feedback loop, activating Per1, Per2, and Cry1 while repressing BMAL1 (PMID:11441147). Its own expression oscillates under control of the nuclear receptors RORα and REV-ERBα acting through RORE elements in the Npas2 promoter (PMID:20817722, PMID:24196956). The heterodimer's DNA-binding activity is gated by cellular redox and gas-sensing inputs: reduced NAD(P)H cofactors strongly enhance binding through a site in the N-terminal bHLH domain (PMID:11441146, PMID:23831463), while both PAS-A and PAS-B domains bind heme as a prosthetic group, and heme-loaded NPAS2:BMAL1 loses DNA binding upon carbon monoxide exposure, which favors inactive BMAL1 homodimers (PMID:12446832); the bHLH domain assists stable heme binding and tunes the PAS-A axial coordination, and mutation of the His119/His171 axial ligands cripples heterodimer formation, E-box binding, and transactivation (PMID:16704425, PMID:18230344, PMID:22245004). CRY1/2 post-translationally regulate the complex by stabilizing unphosphorylated nuclear forms while inhibiting transcriptional activity without disrupting DNA binding (PMID:16628007). NPAS2 functions partially redundantly with CLOCK in both forebrain and peripheral oscillators—double knockout is required to abolish rhythmic peripheral targets, and NPAS2 sustains autonomous rhythms in CLOCK-deficient fibroblasts (PMID:18316400, PMID:26895328)—yet it also has non-redundant roles, particularly in brain reward circuitry where it acts in D1R-expressing accumbens neurons to regulate Drd3 and excitatory transmission and to drive cocaine-conditioned behavior (PMID:25444159, PMID:30962277). At the organismal level NPAS2 governs long-term memory, sleep homeostasis, and food-entrainable behavior (PMID:10864874, PMID:12843397, PMID:16636276). Beyond its core clock role, NPAS2 acts as a direct transcriptional regulator in diverse disease contexts, activating CDC25A, HIF-1α, HES1, and CX3CL1 to promote proliferation, glycolytic metabolic reprogramming, fibrosis, and cell survival (PMID:28333141, PMID:31765736, PMID:31778954, PMID:37406788), and it can stabilize H2AX mRNA to support DNA damage repair (PMID:38291048).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2000 High

    Established NPAS2 as a brain-expressed bHLH-PAS transcription factor with a defined physiological role, answering whether the gene has a non-redundant function in vivo.

    Evidence Targeted lacZ knock-in disrupting the bHLH domain with fear-conditioning behavior in mice

    PMID:10864874

    Open questions at the time
    • Did not identify molecular partners or target genes
    • Mechanism linking NPAS2 to memory not resolved
  2. 2001 High

    Defined the core molecular activity of NPAS2 as an obligate BMAL1 heterodimer that binds E-boxes to activate clock genes, and showed its DNA binding is gated by NAD cofactor redox state—linking transcription to metabolic status.

    Evidence Conditional co-induction cell line with target identification; purified reconstituted DNA-binding assays with NAD(P)H/NAD(P)+ titration

    PMID:11441146 PMID:11441147

    Open questions at the time
    • Physiological source of redox signal in vivo unresolved
    • Structural basis of cofactor enhancement not defined at this stage
  3. 2001 Medium

    Identified nuclear receptor crosstalk by showing RARα/RXRα physically bind NPAS2 and repress its activity, connecting retinoid signaling to clock phase.

    Evidence Co-IP, reporter assays, and phase-shifting experiments in vascular cells

    PMID:11439184

    Open questions at the time
    • Single lab
    • Physiological relevance to central clock not established
  4. 2002 High

    Revealed NPAS2 as a heme- and gas-sensing transcription factor, answering how environmental/metabolic gases could modulate the clock: holo-NPAS2 loses DNA binding under CO via BMAL1 homodimer formation.

    Evidence In vitro heme-binding and CO-titration DNA-binding assays comparing apo vs holo protein

    PMID:12446832

    Open questions at the time
    • In vivo source and concentration of CO acting on NPAS2 unclear
    • Whether heme occupancy is dynamic in cells not addressed
  5. 2003 High

    Demonstrated NPAS2 is required for circadian behavioral outputs and food-entrainable oscillation, establishing it as a functional forebrain clock component.

    Evidence Npas2 knockout mice with locomotor monitoring, polysomnography, and food-restriction paradigm

    PMID:12843397

    Open questions at the time
    • Did not separate forebrain from peripheral contributions
    • Redundancy with CLOCK not yet tested
  6. 2006 Medium

    Resolved the structural basis of heme sensing and defined CRY-mediated post-translational control, showing the bHLH domain assists heme binding and that CRY1/2 stabilize the complex while repressing its activity.

    Evidence Resonance Raman/optical spectroscopy and QCM DNA binding on purified domains; co-expression, localization, reporter, and Cry double-KO tissue analysis

    PMID:16628007 PMID:16704425

    Open questions at the time
    • CRY regulation shown in single lab
    • Coupling between heme state and CRY regulation not integrated
  7. 2006 High

    Placed NPAS2 upstream of activity-dependent Per2 induction in the cortex, mechanistically linking it to NREM sleep homeostasis.

    Evidence EEG recording and sleep deprivation in Npas2 knockout mice with cortical gene expression

    PMID:16636276

    Open questions at the time
    • Direct chromatin mechanism not measured here
    • Cell types responsible not defined
  8. 2008 High

    Pinpointed heme axial ligand residues His119/His171 as essential for heterodimer formation, E-box binding, and transactivation, directly tying heme coordination to transcriptional output.

    Evidence Site-directed mutagenesis with reporter and EMSA assays

    PMID:18230344

    Open questions at the time
    • Whether ligand identity changes dynamically in vivo not shown
  9. 2008 High

    Established functional redundancy with CLOCK in peripheral oscillators via genetic epistasis, answering whether NPAS2 acts only centrally.

    Evidence Clock/Npas2 single and double knockout mice with reporter assays and E-box mutagenesis on the FVII promoter

    PMID:18316400

    Open questions at the time
    • Tissue-specific division of labor between CLOCK and NPAS2 not fully mapped
  10. 2008 Medium

    Extended NPAS2 function beyond timekeeping to the DNA damage response, showing its loss impairs cell cycle delay and repair after mutagen exposure.

    Evidence RNAi depletion with cell cycle analysis, comet assay, and expression arrays

    PMID:18819933

    Open questions at the time
    • Direct target genes not defined here
    • Mechanism of repair regulation unresolved
  11. 2009 Medium

    Provided a genome-wide map of direct NPAS2 targets, broadening its regulon to cancer-relevant genes including CDC25A and CX3CL1.

    Evidence ChIP-on-chip in MCF-7 cells with qPCR validation

    PMID:19457610

    Open questions at the time
    • Functional consequences of most targets not tested
    • Single cell line
  12. 2010 High

    Defined how NPAS2 is wired into the feedback loop, showing RORα/REV-ERBα drive its rhythmic transcription through RORE elements, and confirmed conserved overlapping/distinct roles with CLOCK at the Aanat promoter.

    Evidence ChIP occupancy, RORE mutagenesis, reporter, siRNA; targeted miRNA knockdown and ChIP in chicken photoreceptors

    PMID:20345751 PMID:20817722

    Open questions at the time
    • Quantitative contribution of each regulator to oscillation amplitude not resolved
  13. 2011 Medium

    Connected behavioral state to chromatin, showing sleep deprivation reduces NPAS2/BMAL1 occupancy at the Per2 promoter in vivo, and mapped the NAD(P)H interaction to the N-terminal bHLH region with reduced cofactor as the primary enhancer.

    Evidence In vivo ChIP/qPCR across time of day; EMSA with bHLH truncation mutants

    PMID:22039518 PMID:23831463

    Open questions at the time
    • Signal upstream of occupancy changes not identified
    • NAD(P)H truncation work is single-method/single-lab
  14. 2012 High

    Refined the heme-sensing model by showing the bHLH domain shifts PAS-A axial coordination toward a bis-histidyl His119/His171 state, providing a structural mechanism for interdomain signal transduction.

    Evidence Resonance Raman spectroscopy with mutagenesis of Cys170/His119/His171 on purified bHLH-PAS-A domain

    PMID:22245004

    Open questions at the time
    • Functional consequence of coordination switch in full-length protein in cells not tested
  15. 2016 High

    Demonstrated NPAS2 can sustain autonomous peripheral rhythms independently, answering whether its redundancy with CLOCK extends to cell-autonomous oscillation.

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

    PMID:26895328

    Open questions at the time
    • Why SCN versus peripheral tissues differ in CLOCK/NPAS2 dependence not resolved
  16. 2017 High

    Identified non-redundant NPAS2 functions in the reward system and in cancer cell survival, distinguishing it mechanistically from CLOCK in the accumbens and showing CDC25A activation drives proliferation/anti-apoptosis in HCC.

    Evidence NAc AAV-shRNA knockdown, ChIP-seq, conditioned place preference with CLOCK comparison; ChIP, E-box reporter, Co-IP, and tumor models for CDC25A

    PMID:25444159 PMID:28333141

    Open questions at the time
    • Basis for CLOCK/NPAS2 functional divergence in NAc unknown
    • Whether heme/redox gating operates in these non-clock contexts untested
  17. 2017 Medium

    Expanded NPAS2's reach to GABAergic neurotransmission and characterized weaker ARNTL2/NPAS2 heterodimer activity plus NF-κB-driven induction, broadening its dimerization and regulatory inputs.

    Evidence Npas2 KO and NAc knockdown with behavioral assays and qPCR; HEK293 transfection, RT-qPCR, immunofluorescence, IKK-2 inhibition

    PMID:29163035 PMID:30210560

    Open questions at the time
    • Physiological role of ARNTL2/NPAS2 dimer in vivo unclear
    • Single labs
  18. 2019 High

    Cemented cell-type-specific accumbens function and broadened the disease regulon, showing NPAS2 acts in D1R-MSNs to control excitatory transmission and cocaine plasticity, and activates HIF-1α and HES1 to drive glycolytic reprogramming and fibrosis.

    Evidence Cre-inducible shRNA with electrophysiology and CPP; ChIP/reporter and in vivo models for HIF-1α (HCC) and Hes1 (hepatic stellate cells)

    PMID:30962277 PMID:31765736 PMID:31778954

    Open questions at the time
    • How NPAS2 selects context-specific targets not defined
    • Whether these roles depend on BMAL1 heterodimerization not uniformly tested
  19. 2021 Medium

    Demonstrated cardioprotective NPAS2 activity through CX3CL1 transcriptional activation and autophagy regulation, with a physical CRY2 interaction in cardiomyocytes.

    Evidence Co-IP, CX3CL1 reporter, adenoviral overexpression in a rat ischemia/reperfusion model

    PMID:34460437

    Open questions at the time
    • Single lab
    • Endogenous (non-overexpression) contribution not established
  20. 2022 High

    Linked NPAS2 to xenobiotic metabolism rhythmicity, showing it directly drives diurnal hepatic CYP1A2 expression and enzymatic activity.

    Evidence Npas2 KO mice, ChIP-seq, E-box reporter, and probe-substrate pharmacokinetics

    PMID:36379250

    Open questions at the time
    • Generality across other CYP genes not assessed
  21. 2022 Medium

    Identified SIRT1 as a physical and functional NPAS2 partner in the accumbens, integrating a deacetylase into reward-relevant transcriptional control.

    Evidence Co-IP, overlapping ChIP-seq target analysis, NAc knockdown, and cocaine CPP epistasis

    PMID:35001440

    Open questions at the time
    • Whether SIRT1 deacetylates NPAS2 directly not shown
    • Single lab
  22. 2024 Medium

    Uncovered a non-transcriptional NPAS2 activity—mRNA binding/stabilization of H2AX—mechanistically supporting homology-directed repair and chemoresistance.

    Evidence NPAS2 knockdown, mRNA-seq, γH2AX immunostaining, HDR assay, and in vivo cisplatin treatment in lung adenocarcinoma

    PMID:38291048

    Open questions at the time
    • RNA-binding domain/specificity not mapped
    • Relationship to its DNA-binding clock role unresolved
  23. 2025 Medium

    Extended NPAS2 as a transcriptional repressor of lipid remodeling (LPCAT3) controlling ferroptosis and vascular disease, and a regulator of macrophage glycolysis via FTO/m6A-controlled stability feeding into HIF-1α.

    Evidence VSMC-specific KO mice with ChIP/reporter, lipidomics, ferroptosis assays (preprint); MeRIP-seq and db/db model for FTO/Prrc2a regulation

    PMID:39831513 PMID:bio_10.1101_2025.09.23.677952

    Open questions at the time
    • LPCAT3 study is an unreviewed preprint
    • Whether repression requires BMAL1 heterodimer not addressed
  24. 2026 High

    Defined a circuit-level NPAS2 pathway in mPFC—NPAS2→POU2F2→TH—linking the clock factor to dopamine synthesis control and nap behavior.

    Evidence Region-specific mPFC manipulation, ChIP/reporter, electrophysiology of TH+ neurons, and behavioral nap analysis

    PMID:41839866

    Open questions at the time
    • Whether this pathway requires canonical E-box/BMAL1 dimerization not specified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NPAS2 selects between its canonical BMAL1-dependent E-box transcription and context-specific or non-transcriptional activities (e.g., mRNA stabilization, repression) across tissues remains unresolved, and the in vivo role of heme/redox/CO gating in non-clock disease contexts is undefined.
  • No unified model connecting heme/redox sensing to disease-context targets
  • RNA-binding versus DNA-binding mode switching unexplained
  • Tissue-specific cofactor partner determinants unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0003677 DNA binding 8 GO:0008289 lipid binding 4 GO:0140299 molecular sensor activity 3 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-9909396 Circadian clock 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 2 R-HSA-73894 DNA Repair 2
Partners
ARNTL2BMAL1CRY1CRY2RARARXRASIRT1
Complex memberships
ARNTL2:NPAS2 heterodimerNPAS2:BMAL1 heterodimer

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NPAS2 forms an obligate heterodimer with BMAL1 to bind E-box DNA elements and activate transcription of Per1, Per2, and Cry1 genes while repressing BMAL1; this was demonstrated by conditional co-induction of NPAS2 and BMAL1 in a neuroblastoma cell line with downstream target gene identification. Conditional induction cell line, representational difference analysis, DNA microarrays, Northern blotting Science High 11441147
2001 The DNA-binding activity of NPAS2:BMAL1 heterodimers is regulated by the redox state of NAD cofactors: reduced forms NAD(H) and NADP(H) strongly enhance DNA binding, while oxidized forms inhibit it, demonstrated in a purified reconstituted system. Purified protein DNA-binding assay (electrophoretic mobility shift / in vitro reconstitution) Science High 11441146
2001 Nuclear receptors RARα and RXRα physically interact with NPAS2 (MOP4) and negatively regulate NPAS2/BMAL1-mediated transcriptional activation of clock genes in vascular cells; retinoic acid can phase-shift Per2 mRNA rhythmicity. Co-immunoprecipitation, reporter gene assays, in vivo and in vitro phase-shifting experiments Cell Medium 11439184
2002 Both PAS-A and PAS-B domains of NPAS2 bind heme as a prosthetic group; heme-loaded (holo) NPAS2:BMAL1 heterodimers lose DNA-binding activity upon exposure to low micromolar carbon monoxide, which drives formation of inactive BMAL1 homodimers at the expense of NPAS2:BMAL1 heterodimers; apo-NPAS2 (heme-free) is insensitive to CO. In vitro heme-binding assays, DNA-binding assays with CO titration, reconstituted purified protein system Science High 12446832
2000 NPAS2 is a bHLH-PAS transcription factor expressed in multiple regions of the vertebrate brain; targeted disruption producing an NPAS2-lacZ fusion (lacking the bHLH domain) causes deficits in long-term memory in cued and contextual fear tasks, establishing a functional role in memory acquisition. Targeted gene disruption (lacZ knock-in), behavioral testing (fear conditioning) Science High 10864874
2003 NPAS2-deficient mice show altered locomotor activity, disrupted sleep patterns, and impaired adaptability to food-restricted entrainment, demonstrating that NPAS2 is required for normal circadian behavioral outputs and food-entrainable oscillator function. NPAS2 knockout mouse model, locomotor activity monitoring, polysomnography, food restriction paradigm Science High 12843397
2006 CRY1 and CRY2 stabilize unphosphorylated forms of CLOCK/NPAS2 and BMAL1 and promote their nuclear accumulation, but inhibit their transcriptional activity without affecting NPAS2/BMAL1 complex formation or DNA binding; this establishes CRY-mediated post-translational regulation of the NPAS2/BMAL1 complex. Ectopic co-expression, immunofluorescence localization, reporter assays, analysis of Cry double-KO mouse tissues Cell Cycle Medium 16628007
2006 NPAS2 spectroscopic characterization shows that the bHLH domain assists stable heme binding to the PAS-A domain; the heme-bound bHLH-PAS-A domain dimerizes in solution and binds specifically to E-box DNA sequences only in the presence of heme, as measured by quartz-crystal microbalance. Optical absorption spectroscopy, resonance Raman spectroscopy, heme-binding kinetics, quartz-crystal microbalance DNA-binding assay The FEBS Journal High 16704425
2006 NPAS2 plays a role in non-rapid eye movement sleep homeostasis: Npas2-/- mice show reduced EEG spindle activity during NREMS and altered delta frequency activity; the wake-dependent increase in cortical Per2 expression is attenuated in Npas2-/- mice, placing NPAS2 upstream of Per2 induction by sleep deprivation. Npas2 knockout mice, EEG recording, sleep deprivation, cortical gene expression analysis PNAS High 16636276
2008 Mutation of the heme axial ligand residues His119 or His171 in the PAS-A domain of NPAS2 markedly reduces transcriptional activity of the mouse Per1 promoter and impairs NPAS2:BMAL1 heterodimer formation and E-box DNA binding, establishing these residues as essential for heme-dependent transcriptional control. Site-directed mutagenesis, reporter gene assay (NIH3T3 cells), gel-shift/EMSA Biochemical and Biophysical Research Communications High 18230344
2008 CLOCK and NPAS2 have overlapping roles as transcriptional activators in peripheral (liver) circadian oscillators: FVII mRNA rhythmicity is abolished only in Clock-/-;Npas2-/- double-knockout mice, not in single knockouts; reporter assays confirm both NPAS2:BMAL1 and CLOCK:BMAL1 transactivate the FVII promoter via E-boxes, and this activity is repressed by PER2 and CRY1. Clock/Npas2 single and double knockout mice, reporter gene assays, E-box mutagenesis Molecular and Cellular Biology High 18316400
2008 RNAi-mediated depletion of NPAS2 causes failure of expected cell cycle delay after mutagen treatment and impairs DNA repair capacity (comet assay), and represses expression of multiple cell cycle and DNA repair genes, implicating NPAS2 as a regulator of DNA damage response pathways. RNA interference, cell cycle analysis, comet assay, PCR expression array Molecular Cancer Research Medium 18819933
2009 Genome-wide ChIP-on-chip analysis identified 16 direct transcriptional target genes bound by NPAS2 in MCF-7 cells, including cancer-related genes CDC25A, CDKN2AIP, CX3CL1, ELF4, and others containing NPAS2 binding regions. ChIP-on-chip (chromatin immunoprecipitation coupled to microarray), real-time PCR validation Cancer Letters Medium 19457610
2010 NPAS2 gene expression is directly regulated by the nuclear receptors RORα and REV-ERBα through functional RORE elements in the NPAS2 promoter, coordinating NPAS2 expression with BMAL1 as the positive arm of the circadian feedback loop. ChIP/microarray screen for RORα and REV-ERBα occupancy, RORE mutagenesis, reporter assays, siRNA knockdown Journal of Biological Chemistry High 20817722
2011 Sleep deprivation decreases DNA binding of NPAS2 and BMAL1 to the Per2 promoter in mouse cerebral cortex (by ChIP), demonstrating that sleep-wake history directly modulates NPAS2 chromatin occupancy and thereby alters Per2 expression. Chromatin immunoprecipitation (ChIP), qPCR, time-of-day fractionation PLOS ONE Medium 22039518
2011 The bHLH domain shifts the heme axial coordination in the PAS-A domain of NPAS2 from a Cys170/His119 equilibrium to a predominant His119/His171 bis-histidyl coordination, demonstrating interdomain regulation of heme coordination structure relevant to signal transduction. Resonance Raman spectroscopy, site-directed mutagenesis of Cys170, His119, His171 in bHLH-PAS-A domain Journal of Inorganic Biochemistry High 22245004
2013 The NAD(P)H interaction site of NPAS2 maps to the N-terminal 61 residues of the bHLH domain; this minimal fragment forms a heterodimer with BMAL1 and supports NAD(P)H-enhanced DNA binding; NAD(P)+ does not inhibit NPAS2 DNA binding in this purified system, suggesting enhancement by reduced cofactor is the primary regulatory mechanism. Electrophoretic mobility shift assay (EMSA) with truncation mutants, purified recombinant proteins Biochemical and Biophysical Research Communications Medium 23831463
2013 Circadian transcription of the Npas2 gene is controlled cell-autonomously by RORα binding to a specific RORE in the Npas2 upstream promoter; dominant-negative RORα, RORα siRNA, or RORα-mutant (sg/sg) fibroblasts all dampen Npas2 transcriptional oscillation. Luciferase reporter with RORE mutagenesis, dominant negative construct, siRNA, RORα-mutant mouse embryonic fibroblasts Journal of Biological Chemistry Medium 24196956
2014 NPAS2 directly transcriptionally regulates the Drd3 dopamine receptor gene in the nucleus accumbens (NAc); NPAS2 expression is restricted to Drd1-expressing neurons in the NAc; NPAS2 knockdown in the NAc disrupts Drd3 diurnal rhythm and reduces cocaine conditioned place preference, while CLOCK knockdown in NAc has no effect, revealing a distinct non-redundant role for NPAS2. AAV-shRNA knockdown in NAc, ChIP-seq, cell sorting qRT-PCR, conditioned place preference assay Biological Psychiatry High 25444159
2016 NPAS2 compensates for loss of CLOCK in peripheral circadian oscillators: in CLOCK-deficient fibroblasts, Npas2 knockdown leads to arrhythmicity, demonstrating that NPAS2 maintains autonomous circadian rhythms in peripheral cells (not only in SCN neurons). Single-cell bioluminescence imaging (PER2::LUC), Npas2 siRNA knockdown in CLOCK-deficient fibroblasts PLoS Genetics High 26895328
2017 NPAS2 promotes HCC cell survival by transcriptionally upregulating CDC25A phosphatase through E-box elements in the CDC25A promoter (with BMAL1 as obligate heterodimer), leading to dephosphorylation of CDK2/4/6 (promoting proliferation) and Bcl-2 (inhibiting apoptosis). ChIP, luciferase reporter with E-box mutagenesis, Co-IP (NPAS2-BMAL1 interaction), in vitro and in vivo tumor models Cell Death & Disease High 28333141
2017 NPAS2 is identified as a direct transcriptional target of Gabra genes in striatum; Npas2 null mutant mice show reduced sensitivity to the GABA-A receptor positive allosteric modulator diazepam, and NAc-specific Npas2 knockdown reduces Gabra1 expression, linking NPAS2 to GABAergic neurotransmission. Global Npas2 knockout, NAc-specific AAV-shRNA knockdown, elevated plus maze/light-dark/open field behavioral assays, qPCR Frontiers in Molecular Neuroscience Medium 29163035
2010 CLOCK and NPAS2 both bind the Aanat promoter E-box in situ (by ChIP) in chicken photoreceptors; knockdown of CLOCK reduces circadian expression of Npas2, Per2, and Aanat, while NPAS2 knockdown dampens Aanat rhythm without affecting other clock genes, demonstrating overlapping but hierarchically distinct roles. Gene-specific miRNA knockdown vectors, ChIP, real-time PCR in photoreceptor-enriched cultures Journal of Neurochemistry Medium 20345751
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), promoting Warburg-type glucose metabolism reprogramming in HCC cells. NPAS2 overexpression/knockdown, ChIP, luciferase reporter, in vitro and in vivo metabolic assays Cancer Letters Medium 31765736
2019 NPAS2 contributes to liver fibrosis by directly transcriptionally activating Hes1 (a Notch signaling transcription factor) in hepatic stellate cells, promoting their activation; NPAS2 is upregulated in HSCs after fibrogenic injury. ChIP, luciferase reporter, NPAS2 overexpression/knockdown in HSCs, mouse fibrosis model Molecular Therapy: Nucleic Acids Medium 31778954
2019 NPAS2 expression is restricted to Drd1-expressing D1R-MSNs in the NAc; NPAS2 negatively regulates excitatory synaptic transmission onto D1R-MSNs specifically; cell-type-specific Npas2 knockdown in D1R-MSNs (but not D2R-MSNs) reduces cocaine conditioned place preference and blocks cocaine-induced synaptic potentiation. Cre-inducible shRNA virus, Drd1a-tdTomato mouse line, whole-cell electrophysiology, conditioned place preference Journal of Neuroscience High 30962277
2017 The ARNTL2/NPAS2 heterodimer is a weaker activator of PER3 and DBP than the ARNTL/NPAS2 heterodimer in HEK293 cells; DEC2 blocks the transcriptional effect of the ARNTL2/NPAS2 dimer; TNF induces ARNTL2 nuclear localization and upregulates both ARNTL2 and NPAS2 via NF-κB. Transfection in HEK293 cells, RT-qPCR, immunofluorescence, IKK-2 inhibitor (NF-κB pathway) Journal of Circadian Rhythms Medium 30210560
2022 NPAS2 transcriptionally regulates diurnal expression of hepatic CYP1A2 by binding to an E-box-like element at -416 bp in the Cyp1a2 promoter; Npas2-/- mice show decreased CYP1A2 mRNA, protein, and enzymatic activity with abolished rhythmicity. Npas2 knockout mice, luciferase reporter assays, ChIP-seq, probe substrate pharmacokinetics in vivo Biochemical Pharmacology High 36379250
2022 NPAS2 and SIRT1 physically interact in the nucleus accumbens (by Co-IP); both show diurnal expression in NAc that is altered by cocaine; cross-analysis of NPAS2 and SIRT1 ChIP-seq identifies shared reward-relevant gene targets; NAc-specific Npas2 knockdown attenuates SIRT1-mediated increases in cocaine preference. Co-immunoprecipitation, ChIP-seq, NAc-specific AAV knockdown, cocaine conditioned place preference European Journal of Neuroscience Medium 35001440
2021 NPAS2 interacts with CRY2 (by Co-IP in cardiomyocytes) and directly acts on the CX3CL1 promoter as a transcriptional activator; overexpression of NPAS2 ameliorates myocardial ischemia/reperfusion injury via CX3CL1-AKT/mTOR regulation of autophagy. Co-immunoprecipitation, luciferase reporter (CX3CL1 promoter), adenoviral overexpression, rat I/R model Aging Medium 34460437
2024 NPAS2 enhances the stability of H2AX mRNA by binding to it, thereby upregulating the DNA damage repair pathway (specifically homology-directed repair); depletion of NPAS2 reduces γH2AX accumulation and sensitizes lung adenocarcinoma cells to cisplatin. NPAS2 knockdown, mRNA sequencing, γH2AX immunostaining, HDR assay, in vivo cisplatin treatment Cell Death & Disease Medium 38291048
2023 p53 transcriptionally activates NPAS2 in alveolar type II epithelial cells; NPAS2 in turn promotes epithelial-mesenchymal transition by positively regulating HES1 expression; NPAS2 overexpression weakens the effects of TP53 knockdown on EMT. Reporter assays, siRNA knockdown of TP53/NPAS2, overexpression, mouse bleomycin fibrosis model Cellular Signalling Medium 37406788
2018 Npas2 expression in bone marrow stromal cells (BMSC) is induced by rough-surface Ti implants via α2-adrenergic receptor/cAMP/CREB signaling; Npas2 functional knockout mice show impaired osseointegration of rough-surface implants with abnormal collagen architecture, establishing a neuroskeletal role for NPAS2. Npas2 KO mouse implant model, implant push-out test, high-throughput chemical screen with Npas2-reporter, α2-adrenergic receptor expression analysis Biomaterials Medium 30428407
2025 In vascular smooth muscle cells (VSMCs), NPAS2 transcriptionally represses LPCAT3 (a phospholipid remodeling enzyme); NPAS2 depletion elevates PC-PUFA2S (phosphatidylcholines with two polyunsaturated fatty acyl chains), promoting ferroptosis-induced VSMC phenotypic switching and accelerating ascending thoracic aortic aneurysm; VSMC-specific NPAS2 KO mice exhibit aggravated ATAA. VSMC-specific NPAS2 knockout mice, ChIP/reporter assays (LPCAT3 promoter), lipidomics (PC-PUFA2S), ferroptosis assays, PDGF-BB-treated HASMCs bioRxivpreprint Medium bio_10.1101_2025.09.23.677952
2026 NPAS2 in medial prefrontal cortex (mPFC) transcriptionally activates POU2F2, a transcriptional repressor that downregulates tyrosine hydroxylase (TH) expression, reducing dopamine synthesis in mPFC TH+ neurons during nap hours; mPFC-specific NPAS2 manipulation alters nap behavior in mice. Region-specific NPAS2 manipulation (mPFC), ChIP/reporter for POU2F2-TH pathway, electrophysiology of TH+ neurons, behavioral nap analysis Nature Communications High 41839866
2025 In hypertrophic scar fibroblasts, NPAS2 binds to an E-like-box in the CDC25A promoter to transcriptionally activate CDC25A, promoting fibroblast proliferation and migration; in vivo knockdown of NPAS2 in rat tail wounds inhibits hypertrophic scar formation. Dual-luciferase reporter assay, ChIP, gain/loss-of-function in HDFs and HTS-Fs, in vivo rat wound model with AAV knockdown Journal of Cellular and Molecular Medicine Medium 40548841
2025 FTO (m6A demethylase) reduces m6A modification of Npas2 mRNA through a Prrc2a-dependent mechanism, decreasing Npas2 mRNA stability; Npas2 upregulates HIF-1α signaling to drive M1 macrophage glycolysis and inflammation in diabetic nephropathy. MeRIP-seq, transcriptome analysis, Fto loss/gain-of-function, Prrc2a dependence, db/db mouse model FASEB Journal Medium 39831513

Source papers

Stage 0 corpus · 80 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.) 780 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 368 11439184
2002 NPAS2: a gas-responsive transcription factor. Science (New York, N.Y.) 356 12446832
2003 Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science (New York, N.Y.) 311 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 273 20072116
2007 Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Annals of medicine 204 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 95 22039518
2007 Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk. Breast cancer research and treatment 93 17453337
2016 NPAS2 Compensates for Loss of CLOCK in Peripheral Circadian Oscillators. PLoS genetics 87 26895328
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
2010 ARNTL (BMAL1) and NPAS2 gene variants contribute to fertility and seasonality. PloS one 85 20368993
2008 The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response. Molecular cancer research : MCR 85 18819933
2014 Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biological psychiatry 74 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 67 31765736
2017 NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A. Cell death & disease 57 28333141
2011 Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. Neuropsychobiology 54 21912186
2015 Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia. Fertility and sterility 52 25956372
2015 Association of CLOCK, ARNTL, and NPAS2 gene polymorphisms and seasonal variations in mood and behavior. Chronobiology international 43 26134245
2017 NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors. Frontiers in molecular neuroscience 39 29163035
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 36 38804230
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
2023 NPAS2 promotes aerobic glycolysis and tumor growth in prostate cancer through HIF-1A signaling. BMC cancer 32 36978001
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
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 30 30962277
2021 LncRNA Nuclear-Enriched Abundant Transcript 1 Regulates Atrial Fibrosis via the miR-320/NPAS2 Axis in Atrial Fibrillation. Frontiers in pharmacology 28 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 15 30536616
2022 Involvement of Npas2 and Per2 modifications in zinc-induced acute diurnal toxicity in mice. The Journal of toxicological sciences 14 36450499
2017 DEC2 Blocks the Effect of the ARNTL2/NPAS2 Dimer on the Expression of PER3 and DBP. Journal of circadian rhythms 14 30210560
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 12 39831513
2023 Role of the Circadian Gas-Responsive Hemeprotein NPAS2 in Physiology and Pathology. Biology 12 37887064
2022 Sex-specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal and analgesia. Genes, brain, and behavior 12 36053258
2024 NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair. Cell death & disease 11 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 11 35001440
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
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
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 7 39495286
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
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
2025 NPAS2 Deficiency Leads to Antidepressant-Like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation. Journal of pineal research 3 40820553
2017 Prefrontal cortex and dorsomedial hypothalamus mediate food reward-induced effects via npas2 and egr1 expression in rat. Physiological research 3 29355377
2025 NPAS2 gene variants modulate the circadian preference-depression link in Major Depressive Disorder: A mediation role of sleep and somatic symptoms. Chronobiology international 1 41020491
2026 Impact of NPAS2 on mPFC dopamine synthesis and nap behavior. Nature communications 0 41839866
2026 Peptidylarginine deiminase in Porphyromonas gingivalis-derived outer membrane vesicles exacerbates metabolic dysfunction-associated steatotic liver disease through the NPAS2/CYP4A10 pathway. Journal of nanobiotechnology 0 42106850
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
2024 Sex-specific Regulation of Fentanyl Reward by the Circadian Transcription Factor NPAS2. bioRxiv : the preprint server for biology 0 39605449

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