Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4FS4F5)

• DOT Name: CUGBP Elav-like family member 4 (CELF4)
• Synonyms: CELF-4; Bruno-like protein 4; CUG-BP- and ETR-3-like factor 4; RNA-binding protein BRUNOL-4
• Gene Name: CELF4
• Related Disease:
  Epilepsy
  Anxiety
  Autism
  Autism spectrum disorder
  Endometrial cancer
  Endometrial carcinoma
  Language disorder
  Major depressive disorder
  Mood disorder
  Myocardial infarction
  Obesity
  Cardiomyopathy
  Dental caries
  Nervous system disease
  Non-insulin dependent diabetes
• UniProt ID: CELF4_HUMAN
• PDB ID: 2DGP; 2DNK
• Pfam ID: PF00076
• Sequence:
  MYIKMATLANGQADNASLSTNGLGSSPGSAGHMNGLSHSPGNPSTIPMKDHDAIKLFIGQ
  IPRNLDEKDLKPLFEEFGKIYELTVLKDRFTGMHKGCAFLTYCERESALKAQSALHEQKT
  LPGMNRPIQVKPADSESRGGSSCLRQPPSQDRKLFVGMLNKQQSEDDVRRLFEAFGNIEE
  CTILRGPDGNSKGCAFVKYSSHAEAQAAINALHGSQTMPGASSSLVVKFADTDKERTMRR
  MQQMAGQMGMFNPMAIPFGAYGAYAQALMQQQAALMASVAQGGYLNPMAAFAAAQMQQMA
  ALNMNGLAAAPMTPTSGGSTPPGITAPAVPSIPSPIGVNGFTGLPPQANGQPAAEAVFAN
  GIHPYPAQSPTAADPLQQAYAGVQQYAGPAAYPAAYGQISQAFPQPPPMIPQQQREGPEG
  CNLFIYHLPQEFGDAELMQMFLPFGFVSFDNPASAQTAIQAMNGFQIGMKRLKVQLKRPK
  DANRPY
• Function: RNA-binding protein implicated in the regulation of pre-mRNA alternative splicing. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of cardiac isoforms of TNNT2 during heart remodeling at the juvenile to adult transition. Promotes exclusion of both the smooth muscle (SM) and non-muscle (NM) exons in actinin pre-mRNAs. Activates the splicing of MAPT/Tau exon 10. Binds to muscle-specific splicing enhancer (MSE) intronic sites flanking the alternative exon 5 of TNNT2 pre-mRNA.
• Tissue Specificity: Ubiquitous. Strongly expressed in the cerebellum, hippocampus, amygdala, temporal and frontal cortex and frontal lobes.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Anxiety	DISIJDBA	Strong	Genetic Variation	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[3]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[4]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[4]
Language disorder	DISTLKP7	Strong	Genetic Variation	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[2]
Myocardial infarction	DIS655KI	Strong	Biomarker	[7]
Obesity	DIS47Y1K	Strong	Biomarker	[8]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[9]
Dental caries	DISRBCMD	Limited	Biomarker	[10]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of CUGBP Elav-like family member 4 (CELF4).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CUGBP Elav-like family member 4 (CELF4).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of CUGBP Elav-like family member 4 (CELF4).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CUGBP Elav-like family member 4 (CELF4).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of CUGBP Elav-like family member 4 (CELF4).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of CUGBP Elav-like family member 4 (CELF4).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of CUGBP Elav-like family member 4 (CELF4).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of CUGBP Elav-like family member 4 (CELF4).	[16]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of CUGBP Elav-like family member 4 (CELF4).	[20]

References

• [1] The Functional Communication Classification System: extended reliability and concurrent validity for children with cerebral palsy aged 5 to 18 years.Dev Med Child Neurol. 2019 Jul;61(7):805-812. doi: 10.1111/dmcn.14135. Epub 2019 Jan 6.
• [2] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [3] Familial 18q12.2 deletion supports the role of RNA-binding protein CELF4 in autism spectrum disorders.Am J Med Genet A. 2017 Jun;173(6):1649-1655. doi: 10.1002/ajmg.a.38205. Epub 2017 Apr 13.
• [4] Integrated Epigenomics Analysis Reveals a DNA Methylation Panel for Endometrial Cancer Detection Using Cervical Scrapings.Clin Cancer Res. 2017 Jan 1;23(1):263-272. doi: 10.1158/1078-0432.CCR-16-0863. Epub 2016 Aug 9.
• [5] Schoolchildren with unilateral or mild to moderate bilateral sensorineural hearing loss should be screened for neurodevelopmental problems.Acta Paediatr. 2020 Jul;109(7):1430-1438. doi: 10.1111/apa.15088. Epub 2019 Nov 26.
• [6] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [7] Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia.Mol Psychiatry. 2009 Nov;14(11):1024-31. doi: 10.1038/mp.2008.52. Epub 2008 Jun 3.
• [8] Haploinsufficiency of CELF4 at 18q12.2 is associated with developmental and behavioral disorders, seizures, eye manifestations, and obesity.Eur J Hum Genet. 2012 Dec;20(12):1315-9. doi: 10.1038/ejhg.2012.92. Epub 2012 May 23.
• [9] CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children's Oncology Group Genome-Wide Association Study.J Clin Oncol. 2016 Mar 10;34(8):863-70. doi: 10.1200/JCO.2015.63.4550. Epub 2016 Jan 25.
• [10] Human genes influence the interaction between Streptococcus mutans and host caries susceptibility: a genome-wide association study in children with primary dentition.Int J Oral Sci. 2019 May 30;11(2):19. doi: 10.1038/s41368-019-0051-4.
• [11] CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function.PLoS Genet. 2012;8(11):e1003067. doi: 10.1371/journal.pgen.1003067. Epub 2012 Nov 29.
• [12] Development of GMDR-GPU for gene-gene interaction analysis and its application to WTCCC GWAS data for type 2 diabetes.PLoS One. 2013 Apr 23;8(4):e61943. doi: 10.1371/journal.pone.0061943. Print 2013.
• [13] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [14] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.