Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA3HH6W)

• DOT Name: Neuronal PAS domain-containing protein 4 (NPAS4)
• Synonyms: Neuronal PAS4; Class E basic helix-loop-helix protein 79; bHLHe79; HLH-PAS transcription factor NXF; PAS domain-containing protein 10
• Gene Name: NPAS4
• Related Disease:
  Bipolar depression
  Breast cancer
  Breast carcinoma
  Cerebral infarction
  Depression
  Epilepsy
  Nervous system inflammation
  Neuralgia
  Neurodevelopmental disorder
  Schizophrenia
  Status epilepticus seizure
  Neuroblastoma
  Anxiety
  Anxiety disorder
  Cognitive impairment
  Female hypogonadism
  Intellectual disability
  Stroke
• UniProt ID: NPAS4_HUMAN
• Pfam ID: PF08447
• Sequence:
  MYRSTKGASKARRDQINAEIRNLKELLPLAEADKVRLSYLHIMSLACIYTRKGVFFAGGT
  PLAGPTGLLSAQELEDIVAALPGFLLVFTAEGKLLYLSESVSEHLGHSMVDLVAQGDSIY
  DIIDPADHLTVRQQLTLPSALDTDRLFRCRFNTSKSLRRQSAGNKLVLIRGRFHAHPPGA
  YWAGNPVFTAFCAPLEPRPRPGPGPGPGPASLFLAMFQSRHAKDLALLDISESVLIYLGF
  ERSELLCKSWYGLLHPEDLAHASAQHYRLLAESGDIQAEMVVRLQAKTGGWAWIYCLLYS
  EGPEGPITANNYPISDMEAWSLRQQLNSEDTQAAYVLGTPTMLPSFPENILSQEECSSTN
  PLFTAALGAPRSTSFPSAPELSVVSASEELPRPSKELDFSYLTFPSGPEPSLQAELSKDL
  VCTPPYTPHQPGGCAFLFSLHEPFQTHLPTPSSTLQEQLTPSTATFSDQLTPSSATFPDP
  LTSPLQGQLTETSVRSYEDQLTPCTSTFPDQLLPSTATFPEPLGSPAHEQLTPPSTAFQA
  HLDSPSQTFPEQLSPNPTKTYFAQEGCSFLYEKLPPSPSSPGNGDCTLLALAQLRGPLSV
  DVPLVPEGLLTPEASPVKQSFFHYSEKEQNEIDRLIQQISQLAQGMDRPFSAEAGTGGLE
  PLGGLEPLDSNLSLSGAGPPVLSLDLKPWKCQELDFLADPDNMFLEETPVEDIFMDLSTP
  DPSEEWGSGDPEAEGPGGAPSPCNNLSPEDHSFLEDLATYETAFETGVSAFPYDGFTDEL
  HQLQSQVQDSFHEDGSGGEPTF
• Function: Transcription factor expressed in neurons of the brain that regulates the excitatory-inhibitory balance within neural circuits and is required for contextual memory in the hippocampus. Plays a key role in the structural and functional plasticity of neurons. Acts as an early-response transcription factor in both excitatory and inhibitory neurons, where it induces distinct but overlapping sets of late-response genes in these two types of neurons, allowing the synapses that form on inhibitory and excitatory neurons to be modified by neuronal activity in a manner specific to their function within a circuit, thereby facilitating appropriate circuit responses to sensory experience. In excitatory neurons, activates transcription of BDNF, which in turn controls the number of GABA-releasing synapses that form on excitatory neurons, thereby promoting an increased number of inhibitory synapses on excitatory neurons. In inhibitory neurons, regulates a distinct set of target genes that serve to increase excitatory input onto somatostatin neurons, probably resulting in enhanced feedback inhibition within cortical circuits. The excitatory and inhibitory balance in neurons affects a number of processes, such as short-term and long-term memory, acquisition of experience, fear memory, response to stress and social behavior. Acts as a regulator of dendritic spine development in olfactory bulb granule cells in a sensory-experience-dependent manner by regulating expression of MDM2. Efficient DNA binding requires dimerization with another bHLH protein, such as ARNT, ARNT2 or BMAL1. Can activate the CME (CNS midline enhancer) element.
• Tissue Specificity: Brain.
• Reactome Pathway:
  NPAS4 regulates expression of target genes (R-HSA-9768919)
  Regulation of NPAS4 mRNA translation (R-HSA-9768778)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar depression	DISA75FU	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Cerebral infarction	DISR1WNP	Strong	Altered Expression	[3]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[5]
Nervous system inflammation	DISB3X5A	Strong	Altered Expression	[6]
Neuralgia	DISWO58J	Strong	Biomarker	[7]
Neurodevelopmental disorder	DIS372XH	Strong	Altered Expression	[8]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[8]
Status epilepticus seizure	DISY3BIC	Strong	Altered Expression	[9]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[10]
Anxiety	DISIJDBA	Limited	Biomarker	[11]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[11]
Cognitive impairment	DISH2ERD	Limited	Altered Expression	[8]
Female hypogonadism	DISWASB4	Limited	Genetic Variation	[12]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[12]
Stroke	DISX6UHX	Limited	Biomarker	[11]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Neuronal PAS domain-containing protein 4 (NPAS4).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Neuronal PAS domain-containing protein 4 (NPAS4).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Neuronal PAS domain-containing protein 4 (NPAS4).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Neuronal PAS domain-containing protein 4 (NPAS4).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Neuronal PAS domain-containing protein 4 (NPAS4).	[17]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neuronal PAS domain-containing protein 4 (NPAS4).	[18]

References

• [1] Effects of Npas4 deficiency on anxiety, depression-like, cognition and sociability behaviour.Behav Brain Res. 2015 Mar 15;281:276-82. doi: 10.1016/j.bbr.2014.12.044. Epub 2014 Dec 27.
• [2] Growth of Triple Negative and Progesterone Positive Breast Cancer Causes Oxidative Stress and Down-Regulates Neuroprotective Transcription Factor NPAS4 and NPAS4-Regulated Genes in Hippocampal Tissues of TumorGraft Mice-an Aging Connection.Front Genet. 2018 Mar 5;9:58. doi: 10.3389/fgene.2018.00058. eCollection 2018.
• [3] The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia.Int J Mol Sci. 2015 Dec 4;16(12):29011-28. doi: 10.3390/ijms161226144.
• [4] Multiple sequences orchestrate subcellular trafficking of neuronal PAS domain-containing protein 4 (NPAS4).J Biol Chem. 2018 Jul 20;293(29):11255-11270. doi: 10.1074/jbc.RA118.001812. Epub 2018 Jun 13.
• [5] Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epilepsy through the induction of Homer1a.J Neurochem. 2018 Apr;145(1):19-33. doi: 10.1111/jnc.14274. Epub 2017 Dec 28.
• [6] Expression of the neuroprotective protein aryl hydrocarbon receptor nuclear translocator 2 correlates with neuronal stress and disability in models of multiple sclerosis.J Neuroinflammation. 2018 Sep 19;15(1):270. doi: 10.1186/s12974-018-1290-6.
• [7] Environmental enrichment improves pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain: role of NPAS4.Psychopharmacology (Berl). 2019 Jul;236(7):1999-2014. doi: 10.1007/s00213-019-5187-6. Epub 2019 Feb 23.
• [8] Downregulation of Npas4 in parvalbumin interneurons and cognitive deficits after neonatal NMDA receptor blockade: relevance for schizophrenia.Transl Psychiatry. 2019 Feb 21;9(1):99. doi: 10.1038/s41398-019-0436-3.
• [9] RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis.Sci Rep. 2017 Jan 27;7:41517. doi: 10.1038/srep41517.
• [10] Variants in RET associated with Hirschsprung's disease affect binding of transcription factors and gene expression.Gastroenterology. 2011 Feb;140(2):572-582.e2. doi: 10.1053/j.gastro.2010.10.044. Epub 2010 Oct 25.
• [11] Alterations in anxiety and social behaviour in Npas4 deficient mice following photochemically-induced focal cortical stroke.Behav Brain Res. 2017 Jan 1;316:29-37. doi: 10.1016/j.bbr.2016.08.050. Epub 2016 Aug 26.
• [12] De novo duplication of Xq22.1q24 with a disruption of the NXF gene cluster in a mentally retarded woman with short stature and premature ovarian failure.Taiwan J Obstet Gynecol. 2011 Sep;50(3):339-44. doi: 10.1016/j.tjog.2011.01.018.
• [13] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [16] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.