Details of Drug Off-Target (DOT)

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

• DOT Name: Transcription factor GATA-4 (GATA4)
• Synonyms: GATA-binding factor 4
• Gene Name: GATA4
• Related Disease:
  Atrial septal defect 2
  Structural congenital heart disease, multiple types - GATA4
  Testicular anomalies with or without congenital heart disease
  Neonatal diabetes mellitus
  Obsolete metabolic syndrome
  Pancreatic hypoplasia-diabetes-congenital heart disease syndrome
  Permanent neonatal diabetes mellitus
  Transient neonatal diabetes mellitus
  46,XY partial gonadal dysgenesis
  Familial atrial fibrillation
  Tetralogy of fallot
  Dilated cardiomyopathy
• UniProt ID: GATA4_HUMAN
• PDB ID: 2M9W
• Pfam ID: PF00320 ; PF05349
• Sequence:
  MYQSLAMAANHGPPPGAYEAGGPGAFMHGAGAASSPVYVPTPRVPSSVLGLSYLQGGGAG
  SASGGASGGSSGGAASGAGPGTQQGSPGWSQAGADGAAYTPPPVSPRFSFPGTTGSLAAA
  AAAAAAREAAAYSSGGGAAGAGLAGREQYGRAGFAGSYSSPYPAYMADVGASWAAAAAAS
  AGPFDSPVLHSLPGRANPAARHPNLDMFDDFSEGRECVNCGAMSTPLWRRDGTGHYLCNA
  CGLYHKMNGINRPLIKPQRRLSASRRVGLSCANCQTTTTTLWRRNAEGEPVCNACGLYMK
  LHGVPRPLAMRKEGIQTRKRKPKNLNKSKTPAAPSGSESLPPASGASSNSSNATTSSSEE
  MRPIKTEPGLSSHYGHSSSVSQTFSVSAMSGHGPSIHPVLSALKLSPQGYASPVSQSPQT
  SSKQDSWNSLVLADSHGDIITA
• Function: Transcriptional activator that binds to the consensus sequence 5'-AGATAG-3' and plays a key role in cardiac development and function. In cooperation with TBX5, it binds to cardiac super-enhancers and promotes cardiomyocyte gene expression, while it down-regulates endocardial and endothelial gene expression. Involved in bone morphogenetic protein (BMP)-mediated induction of cardiac-specific gene expression. Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions. Acts as a transcriptional activator of ANF in cooperation with NKX2-5. Promotes cardiac myocyte enlargement. Required during testicular development. May play a role in sphingolipid signaling by regulating the expression of sphingosine-1-phosphate degrading enzyme, sphingosine-1-phosphate lyase.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Cellular senescence (hsa04218)
  Tight junction (hsa04530)
  Thyroid hormone sig.ling pathway (hsa04919)
• Reactome Pathway:
  Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) (R-HSA-400511)
  Physiological factors (R-HSA-5578768)
  Transcriptional regulation of testis differentiation (R-HSA-9690406)
  Cardiogenesis (R-HSA-9733709)
  Formation of lateral plate mesoderm (R-HSA-9758920)
  Formation of definitive endoderm (R-HSA-9823730)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial septal defect 2	DIS12IDK	Definitive	Autosomal dominant	[1]
Structural congenital heart disease, multiple types - GATA4	DISKENQD	Definitive	Autosomal dominant	[2]
Testicular anomalies with or without congenital heart disease	DISVX3P2	Definitive	Autosomal dominant	[3]
Neonatal diabetes mellitus	DISFHF9K	Strong	Autosomal dominant	[4]
Obsolete metabolic syndrome	DISH33EG	Strong	Autosomal dominant	[4]
Pancreatic hypoplasia-diabetes-congenital heart disease syndrome	DISR6WPA	Strong	Autosomal dominant	[4]
Permanent neonatal diabetes mellitus	DIS5AEXS	Strong	Autosomal dominant	[4]
Transient neonatal diabetes mellitus	DIST826V	Strong	Autosomal dominant	[4]
46,XY partial gonadal dysgenesis	DISMNH0C	Supportive	Autosomal dominant	[5]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[6]
Tetralogy of fallot	DISMHFNW	Supportive	Autosomal dominant	[7]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Warfarin	DMJYCVW	Approved	Transcription factor GATA-4 (GATA4) affects the response to substance of Warfarin.	[23]

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 Transcription factor GATA-4 (GATA4).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transcription factor GATA-4 (GATA4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transcription factor GATA-4 (GATA4).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Transcription factor GATA-4 (GATA4).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription factor GATA-4 (GATA4).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transcription factor GATA-4 (GATA4).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transcription factor GATA-4 (GATA4).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription factor GATA-4 (GATA4).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Transcription factor GATA-4 (GATA4).	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Transcription factor GATA-4 (GATA4).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Transcription factor GATA-4 (GATA4).	[14]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Transcription factor GATA-4 (GATA4).	[17]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Transcription factor GATA-4 (GATA4).	[17]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin decreases the expression of Transcription factor GATA-4 (GATA4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transcription factor GATA-4 (GATA4).	[20]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Transcription factor GATA-4 (GATA4).	[21]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Transcription factor GATA-4 (GATA4).	[22]

References

• [1] Spectrum of heart disease associated with murine and human GATA4 mutation. J Mol Cell Cardiol. 2007 Dec;43(6):677-85. doi: 10.1016/j.yjmcc.2007.06.004. Epub 2007 Jun 21.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Loss-of-function mutation in GATA4 causes anomalies of human testicular development. Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1597-602. doi: 10.1073/pnas.1010257108. Epub 2011 Jan 10.
• [6] GATA4 loss-of-function mutations in familial atrial fibrillation. Clin Chim Acta. 2011 Sep 18;412(19-20):1825-30. doi: 10.1016/j.cca.2011.06.017. Epub 2011 Jun 25.
• [7] GATA4 loss-of-function mutations underlie familial tetralogy of fallot. Hum Mutat. 2013 Dec;34(12):1662-71. doi: 10.1002/humu.22434. Epub 2013 Sep 17.
• [8] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [9] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] 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.
• [12] Arsenic induces human chondrocyte senescence and accelerates rat articular cartilage aging. Arch Toxicol. 2020 Jan;94(1):89-101. doi: 10.1007/s00204-019-02607-2. Epub 2019 Nov 16.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [15] 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.
• [16] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [17] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [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] Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity. Toxicology. 2020 Apr 15;435:152422. doi: 10.1016/j.tox.2020.152422. Epub 2020 Feb 26.
• [20] Peroxisome proliferator-activated receptor-gamma mediates bisphenol A inhibition of FSH-stimulated IGF-1, aromatase, and estradiol in human granulosa cells. Environ Health Perspect. 2010 Mar;118(3):400-6. doi: 10.1289/ehp.0901161. Epub 2009 Oct 22.
• [21] Alteration of estrogen-regulated gene expression in human cells induced by the agricultural and horticultural herbicide glyphosate. Hum Exp Toxicol. 2007 Sep;26(9):747-52. doi: 10.1177/0960327107083453.
• [22] Low-dose tributyltin triggers human chondrocyte senescence and mouse articular cartilage aging. Arch Toxicol. 2023 Feb;97(2):547-559. doi: 10.1007/s00204-022-03407-x. Epub 2022 Nov 1.
• [23] Genetic variations in the transcription factors GATA4 and GATA6 and bleeding complications in patients receiving warfarin therapy. Drug Des Devel Ther. 2019 May 17;13:1717-1727. doi: 10.2147/DDDT.S198018. eCollection 2019.