Details of Drug Off-Target (DOT)

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

• DOT Name: Zinc finger protein Eos (IKZF4)
• Synonyms: Ikaros family zinc finger protein 4
• Gene Name: IKZF4
• Related Disease:
  Alopecia areata
  Autoimmune disease
  Type-1 diabetes
  Asthma
  Vitiligo
• UniProt ID: IKZF4_HUMAN
• PDB ID: 2MA7
• Pfam ID: PF00096
• Sequence:
  MHTPPALPRRFQGGGRVRTPGSHRQGKDNLERDPSGGCVPDFLPQAQDSNHFIMESLFCE
  SSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLL
  EKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRS
  HTGERPFHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCNYACRRRDALTGHLRTHSVS
  SPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQPGDEIRDLEMVPD
  SMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELV
  AHHSLEPGFGSSLAFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLPGRLELPGSRE
  AGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGVVSLPQGPPPQ
  PPPTIVVGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRVVGESGEPVKAFKCEHCRILFL
  DHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG
• Function: DNA-binding protein that binds to the 5'GGGAATRCC-3' Ikaros-binding sequence. Transcriptional repressor. Interacts with SPI1 and MITF to repress transcription of the CTSK and ACP5 promoters via recruitment of corepressors SIN3A and CTBP2. May be involved in the development of central and peripheral nervous systems. Essential for the inhibitory function of regulatory T-cells (Treg). Mediates FOXP3-mediated gene silencing in regulatory T-cells (Treg) via recruitment of corepressor CTBP1.
• Tissue Specificity: Highly expressed in skeletal muscle, low levels of expression in heart, thymus, kidney, liver, and spleen. Expressed in the hematopoietic cell lines MOLT-4, NALM-6 and K-562. Highly expressed in THP-1 and M-07e cell lines, which have characteristics of myeloid and early megakaryocytic cells respectively.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alopecia areata	DIS0XXBJ	Strong	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[3]
Asthma	DISW9QNS	moderate	Genetic Variation	[4]
Vitiligo	DISR05SL	moderate	Genetic Variation	[5]

3 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 Zinc finger protein Eos (IKZF4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Zinc finger protein Eos (IKZF4).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Zinc finger protein Eos (IKZF4).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Marinol increases the expression of Zinc finger protein Eos (IKZF4).	[7]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Zinc finger protein Eos (IKZF4).	[10]

References

• [1] Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.Nature. 2010 Jul 1;466(7302):113-7. doi: 10.1038/nature09114.
• [2] Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity.J Autoimmun. 2019 Dec;105:102300. doi: 10.1016/j.jaut.2019.06.011. Epub 2019 Jul 8.
• [3] Associations of polymorphisms in non-HLA loci with autoantibodies at the diagnosis of type 1 diabetes: INS and IKZF4 associate with insulin autoantibodies.Pediatr Diabetes. 2013 Nov;14(7):490-6. doi: 10.1111/pedi.12046. Epub 2013 May 31.
• [4] Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population.Nat Genet. 2011 Jul 31;43(9):893-6. doi: 10.1038/ng.887.
• [5] Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.
• [6] 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.
• [7] 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.
• [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] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [10] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.