Details of Drug Off-Target (DOT)

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

• DOT Name: Hepatocyte nuclear factor 4-gamma (HNF4G)
• Synonyms: HNF-4-gamma; Nuclear receptor subfamily 2 group A member 2
• Gene Name: HNF4G
• Related Disease:
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Gout
  Ulcerative colitis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Lung cancer
  Lung carcinoma
  Neoplasm
  Type-1/2 diabetes
• UniProt ID: HNF4G_HUMAN
• PDB ID: 1LV2
• Pfam ID: PF00104 ; PF00105
• Sequence:
  MNTTDNGVNCLCAICGDRATGKHYGASSCDGCKGFFRRSIRKSHVYSCRFSRQCVVDKDK
  RNQCRYCRLRKCFRAGMKKEAVQNERDRISTRRSTFDGSNIPSINTLAQAEVRSRQISVS
  SPGSSTDINVKKIASIGDVCESMKQQLLVLVEWAKYIPAFCELPLDDQVALLRAHAGEHL
  LLGATKRSMMYKDILLLGNNYVIHRNSCEVEISRVANRVLDELVRPFQEIQIDDNEYACL
  KAIVFFDPDAKGLSDPVKIKNMRFQVQIGLEDYINDRQYDSRGRFGELLLLLPTLQSITW
  QMIEQIQFVKLFGMVKIDNLLQEMLLGGASNDGSHLHHPMHPHLSQDPLTGQTILLGPMS
  TLVHADQISTPETPLPSPPQGSGQEQYKIAANQASVISHQHLSKQKQL
• Function: Transcription factor. Has a lower transcription activation potential than HNF4-alpha.
• Tissue Specificity: Expressed in pancreas, kidney, small intestine and testis. Weakly expressed in colon. Not expressed in liver, skeletal muscle, lung, placenta, brain, heart, peripheral blood, ovary, prostate, thymus and spleen.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Gout	DISHC0U7	Strong	Genetic Variation	[4]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[5]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	moderate	Biomarker	[1]
Lung carcinoma	DISTR26C	moderate	Biomarker	[1]
Neoplasm	DISZKGEW	moderate	Altered Expression	[1]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[6]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Uric acid	DMA1MKT	Investigative	Hepatocyte nuclear factor 4-gamma (HNF4G) affects the abundance of Uric acid.	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Hepatocyte nuclear factor 4-gamma (HNF4G).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Hepatocyte nuclear factor 4-gamma (HNF4G).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hepatocyte nuclear factor 4-gamma (HNF4G).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hepatocyte nuclear factor 4-gamma (HNF4G).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Hepatocyte nuclear factor 4-gamma (HNF4G).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Hepatocyte nuclear factor 4-gamma (HNF4G).	[11]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Hepatocyte nuclear factor 4-gamma (HNF4G).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hepatocyte nuclear factor 4-gamma (HNF4G).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hepatocyte nuclear factor 4-gamma (HNF4G).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Hepatocyte nuclear factor 4-gamma (HNF4G).	[15]

References

• [1] Expression of HNF4G and its potential functions in lung cancer.Oncotarget. 2017 Dec 4;9(26):18018-18028. doi: 10.18632/oncotarget.22933. eCollection 2018 Apr 6.
• [2] Large-scale genotyping identifies 41 new loci associated with breast cancer risk.Nat Genet. 2013 Apr;45(4):353-61, 361e1-2. doi: 10.1038/ng.2563.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [5] Genome-wide gene expression differences in Crohn's disease and ulcerative colitis from endoscopic pinch biopsies: insights into distinctive pathogenesis.Inflamm Bowel Dis. 2007 Jul;13(7):807-21. doi: 10.1002/ibd.20110.
• [6] No diabetes-associated mutations in the coding region of the hepatocyte nuclear factor-4gamma gene (HNF4G) in Japanese patients with MODY.Diabetologia. 2000 Aug;43(8):1064-9. doi: 10.1007/s001250051491.
• [7] 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.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [13] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.