Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor RFX4 (RFX4)
• Synonyms: Regulatory factor X 4; Testis development protein NYD-SP10
• Gene Name: RFX4
• Related Disease:
  Bipolar disorder
  Alcohol dependence
  Congenital hydrocephalus
  Holoprosencephaly
• UniProt ID: RFX4_HUMAN
• Pfam ID: PF02257
• Sequence:
  MHCGLLEEPDMDSTESWIERCLNESENKRYSSHTSLGNVSNDENEEKENNRASKPHSTPA
  TLQWLEENYEIAEGVCIPRSALYMHYLDFCEKNDTQPVNAASFGKIIRQQFPQLTTRRLG
  TRGQSKYHYYGIAVKESSQYYDVMYSKKGAAWVSETGKKEVSKQTVAYSPRSKLGTLLPE
  FPNVKDLNLPASLPEEKVSTFIMMYRTHCQRILDTVIRANFDEVQSFLLHFWQGMPPHML
  PVLGSSTVVNIVGVCDSILYKAISGVLMPTVLQALPDSLTQVIRKFAKQLDEWLKVALHD
  LPENLRNIKFELSRRFSQILRRQTSLNHLCQASRTVIHSADITFQMLEDWRNVDLNSITK
  QTLYTMEDSRDEHRKLITQLYQEFDHLLEEQSPIESYIEWLDTMVDRCVVKVAAKRQGSL
  KKVAQQFLLMWSCFGTRVIRDMTLHSAPSFGSFHLIHLMFDDYVLYLLESLHCQERANEL
  MRAMKGEGSTAEVREEIILTEAAAPTPSPVPSFSPAKSATSVEVPPPSSPVSNPSPEYTG
  LSTTGAMQSYTWSLTYTVTTAAGSPAENSQQLPCMRNTHVPSSSVTHRIPVYPHREEHGY
  TGSYNYGSYGNQHPHPMQSQYPALPHDTAISGPLHYAPYHRSSAQYPFNSPTSRMEPCLM
  SSTPRLHPTPVTPRWPEVPSANTCYTSPSVHSARYGNSSDMYTPLTTRRNSEYEHMQHFP
  GFAYINGEASTGWAK
• Function: Transcription factor that plays a role in early brain development. May activate transcription by interacting directly with the X-box. May activate transcription from CX3CL1 promoter through the X-box during brain development. May be required for neural tube ciliogenesis during embryogenesis.
• Tissue Specificity: Isoform 1: Expressed in brain and gliomas (at protein level). Isoform 2: Testis-specific (at protein level). Isoform 3: Testis-specific (at protein level). Isoform 3: Expressed at a higher level in adult testes and ejaculated spermatozoa than in fetal testes. Isoform 4: Testis-specific.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[2]
Congenital hydrocephalus	DIS7O6UL	Strong	Genetic Variation	[3]
Holoprosencephaly	DISR35EC	Strong	Biomarker	[3]

2 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 Transcription factor RFX4 (RFX4).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transcription factor RFX4 (RFX4).	[8]

4 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 Transcription factor RFX4 (RFX4).	[5]
Marinol	DM70IK5	Approved	Marinol increases the expression of Transcription factor RFX4 (RFX4).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transcription factor RFX4 (RFX4).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor RFX4 (RFX4).	[9]

References

• [1] Regulatory factor X4 variant 3: a transcription factor involved in brain development and disease.J Neurosci Res. 2007 Dec;85(16):3515-22. doi: 10.1002/jnr.21356.
• [2] Polymorphisms in ABLIM1 are associated with personality traits and alcohol dependence.J Mol Neurosci. 2012 Feb;46(2):265-71. doi: 10.1007/s12031-011-9530-6. Epub 2011 May 6.
• [3] Conditional ablation of the RFX4 isoform 1 transcription factor: Allele dosage effects on brain phenotype.PLoS One. 2018 Jan 3;13(1):e0190561. doi: 10.1371/journal.pone.0190561. eCollection 2018.
• [4] 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.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] 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.
• [8] 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.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.