Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTON40EJ)

• DOT Name: Protein HIRA (HIRA)
• Synonyms: TUP1-like enhancer of split protein 1
• Gene Name: HIRA
• Related Disease:
  Arthropathy
  Neoplasm
  Non-insulin dependent diabetes
  Alopecia totalis
  DiGeorge syndrome
  Herpes simplex infection
  Malignant soft tissue neoplasm
  Osteoporosis
  Progressive multifocal leukoencephalopathy
  Sarcoma
  Shprintzen-Goldberg syndrome
  Tetralogy of fallot
  Meningioma
  Velocardiofacial syndrome
  Congenital heart disease
  Intellectual disability
  Venous thromboembolism
• UniProt ID: HIRA_HUMAN
• PDB ID: 2I32; 5YJE
• Pfam ID: PF07569 ; PF00400
• Sequence:
  MKLLKPTWVNHNGKPIFSVDIHPDGTKFATGGQGQDSGKVVIWNMSPVLQEDDEKDENIP
  KMLCQMDNHLACVNCVRWSNSGMYLASGGDDKLIMVWKRATYIGPSTVFGSSGKLANVEQ
  WRCVSILRNHSGDVMDVAWSPHDAWLASCSVDNTVVIWNAVKFPEILATLRGHSGLVKGL
  TWDPVGKYIASQADDRSLKVWRTLDWQLETSITKPFDECGGTTHVLRLSWSPDGHYLVSA
  HAMNNSGPTAQIIEREGWKTNMDFVGHRKAVTVVKFNPKIFKKKQKNGSSAKPSCPYCCC
  AVGSKDRSLSVWLTCLKRPLVVIHELFDKSIMDISWTLNGLGILVCSMDGSVAFLDFSQD
  ELGDPLSEEEKSRIHQSTYGKSLAIMTEAQLSTAVIENPEMLKYQRRQQQQQLDQKSAAT
  REMGSATSVAGVVNGESLEDIRKNLLKKQVETRTADGRRRITPLCIAQLDTGDFSTAFFN
  SIPLSGSLAGTMLSSHSSPQLLPLDSSTPNSFGASKPCTEPVVAASARPAGDSVNKDSMN
  ATSTPAALSPSVLTTPSKIEPMKAFDSRFTERSKATPGAPALTSMTPTAVERLKEQNLVK
  ELRPRDLLESSSDSDEKVPLAKASSLSKRKLELEVETVEKKKKGRPRKDSRLMPVSLSVQ
  SPAALTAEKEAMCLSAPALALKLPIPSPQRAFTLQVSSDPSMYIEVENEVTVVGGVKLSR
  LKCNREGKEWETVLTSRILTAAGSCDVVCVACEKRMLSVFSTCGRRLLSPILLPSPISTL
  HCTGSYVMALTAAATLSVWDVHRQVVVVKEESLHSILAGSDMTVSQILLTQHGIPVMNLS
  DGKAYCFNPSLSTWNLVSDKQDSLAQCADFRSSLPSQDAMLCSGPLAIIQGRTSNSGRQA
  ARLFSVPHVVQQETTLAYLENQVAAALTLQSSHEYRHWLLVYARYLVNEGFEYRLREICK
  DLLGPVHYSTGSQWESTVVGLRKRELLKELLPVIGQNLRFQRLFTECQEQLDILRDK
• Function: Cooperates with ASF1A to promote replication-independent chromatin assembly. Required for the periodic repression of histone gene transcription during the cell cycle. Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit.
• Tissue Specificity: Expressed at high levels in kidney, pancreas and skeletal muscle and at lower levels in brain, heart, liver, lung, and placenta.
• Reactome Pathway:
  Replacement of protamines by nucleosomes in the male pronucleus (R-HSA-9821993)
  Formation of Senescence-Associated Heterochromatin Foci (SAHF) (R-HSA-2559584)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthropathy	DISVEERK	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[3]
Alopecia totalis	DISCNJPF	Strong	Genetic Variation	[4]
DiGeorge syndrome	DIST1RKO	Strong	Genetic Variation	[5]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[6]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[7]
Osteoporosis	DISF2JE0	Strong	Biomarker	[8]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[9]
Sarcoma	DISZDG3U	Strong	Biomarker	[7]
Shprintzen-Goldberg syndrome	DISQH6P3	Strong	Biomarker	[10]
Tetralogy of fallot	DISMHFNW	Strong	Biomarker	[11]
Meningioma	DISPT4TG	moderate	Genetic Variation	[12]
Velocardiofacial syndrome	DISOSBTY	moderate	Genetic Variation	[13]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[14]
Intellectual disability	DISMBNXP	Limited	Altered Expression	[15]
Venous thromboembolism	DISUR7CR	Limited	Genetic Variation	[16]

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 Protein HIRA (HIRA).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein HIRA (HIRA).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein HIRA (HIRA).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein HIRA (HIRA).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein HIRA (HIRA).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein HIRA (HIRA).	[21]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Protein HIRA (HIRA).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein HIRA (HIRA).	[23]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Protein HIRA (HIRA).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protein HIRA (HIRA).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein HIRA (HIRA).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein HIRA (HIRA).	[27]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Protein HIRA (HIRA).	[28]
Biotin	DMKMCE1	Investigative	Biotin decreases the expression of Protein HIRA (HIRA).	[29]

References

• [1] Use of Western Medicine and Traditional Korean Medicine for Joint Disorders: A Retrospective Comparative Analysis Based on Korean Nationwide Insurance Data.Evid Based Complement Alternat Med. 2017;2017:2038095. doi: 10.1155/2017/2038095. Epub 2017 Dec 6.
• [2] HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia.Genes Dev. 2014 Dec 15;28(24):2712-25. doi: 10.1101/gad.247528.114.
• [3] Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation.Diabetologia. 1994 Sep;37 Suppl 2:S149-54. doi: 10.1007/BF00400838.
• [4] Clinical and molecular diagnostic criteria of congenital atrichia with papular lesions.J Invest Dermatol. 2001 Dec;117(6):1662-5. doi: 10.1046/j.0022-202x.2001.01618.x.
• [5] Multiplexed quantitative real-time PCR to detect 22q11.2 deletion in patients with congenital heart disease.Physiol Genomics. 2010 Sep;42A(1):52-60. doi: 10.1152/physiolgenomics.00073.2010. Epub 2010 Jun 15.
• [6] The histone chaperone HIRA promotes the induction of host innate immune defences in response to HSV-1 infection.PLoS Pathog. 2019 Mar 22;15(3):e1007667. doi: 10.1371/journal.ppat.1007667. eCollection 2019 Mar.
• [7] Activation of transforming potential of the human insulin receptor gene.Proc Natl Acad Sci U S A. 1987 Aug;84(16):5725-9. doi: 10.1073/pnas.84.16.5725.
• [8] Identification of potential pathogenic genes associated with osteoporosis.Bone Joint Res. 2017 Dec;6(12):640-648. doi: 10.1302/2046-3758.612.BJR-2017-0102.R1.
• [9] PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX.Genome Res. 2017 Jun;27(6):913-921. doi: 10.1101/gr.215830.116. Epub 2017 Mar 24.
• [10] Prenatal diagnosis of an unexpected interstitial 22q11.2 deletion causing truncus arteriosus and thymic hypoplasia in a ring 22 chromosome derived from a maternally inherited paracentric inversion.Prenat Diagn. 2006 Dec;26(13):1212-5. doi: 10.1002/pd.1590.
• [11] HIRA Gene is Lower Expressed in the Myocardium of Patients with Tetralogy of Fallot.Chin Med J (Engl). 2016 Oct 20;129(20):2403-2408. doi: 10.4103/0366-6999.191745.
• [12] Chromosomal and genetic abnormalities in benign and malignant meningiomas using DNA microarray.Neurol Res. 2005 Oct;27(7):747-54. doi: 10.1179/016164105X35648.
• [13] De novo unbalanced translocation t(15;22)(q26.2;q12) with velo-cardio-facial syndrome: A case report and review of the literature.Exp Ther Med. 2018 Oct;16(4):3589-3595. doi: 10.3892/etm.2018.6609. Epub 2018 Aug 16.
• [14] HIRA directly targets the enhancers of selected cardiac transcription factors during in vitro differentiation of mouse embryonic stem cells.Mol Biol Rep. 2018 Oct;45(5):1001-1011. doi: 10.1007/s11033-018-4247-z. Epub 2018 Jul 20.
• [15] Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3.EMBO Rep. 2015 Apr;16(4):528-38. doi: 10.15252/embr.201439092. Epub 2015 Feb 9.
• [16] Venous thromboembolism in relapsed or refractory multiple myeloma patients treated with lenalidomide plus dexamethasone.Int J Hematol. 2019 Jan;109(1):79-90. doi: 10.1007/s12185-018-2540-1. Epub 2018 Oct 5.
• [17] 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.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [22] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [23] 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.
• [24] 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.
• [25] Benzo[a]pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci. 2010 Aug;116(2):549-61.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Clusters of biotin-responsive genes in human peripheral blood mononuclear cells. J Nutr Biochem. 2004 Jul;15(7):433-9.