Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3UK5KE)

• DOT Name: T-box transcription factor TBX21 (TBX21)
• Synonyms: T-box protein 21; T-cell-specific T-box transcription factor T-bet; Transcription factor TBLYM
• Gene Name: TBX21
• Related Disease: Immunodeficiency 88
• UniProt ID: TBX21_HUMAN
• Pfam ID: PF00907
• Sequence:
  MGIVEPGCGDMLTGTEPMPGSDEGRAPGADPQHRYFYPEPGAQDADERRGGGSLGSPYPG
  GALVPAPPSRFLGAYAYPPRPQAAGFPGAGESFPPPADAEGYQPGEGYAAPDPRAGLYPG
  PREDYALPAGLEVSGKLRVALNNHLLWSKFNQHQTEMIITKQGRRMFPFLSFTVAGLEPT
  SHYRMFVDVVLVDQHHWRYQSGKWVQCGKAEGSMPGNRLYVHPDSPNTGAHWMRQEVSFG
  KLKLTNNKGASNNVTQMIVLQSLHKYQPRLHIVEVNDGEPEAACNASNTHIFTFQETQFI
  AVTAYQNAEITQLKIDNNPFAKGFRENFESMYTSVDTSIPSPPGPNCQFLGGDHYSPLLP
  NQYPVPSRFYPDLPGQAKDVVPQAYWLGAPRDHSYEAEFRAVSMKPAFLPSAPGPTMSYY
  RGQEVLAPGAGWPVAPQYPPKMGPASWFRPMRTLPMEPGPGGSEGRGPEDQGPPLVWTEI
  APIRPESSDSGLGEGDSKRRRVSPYPSSGDSSSPAGAPSPFDKEAEGQFYNYFPN
• Function: Lineage-defining transcription factor which initiates Th1 lineage development from naive Th precursor cells both by activating Th1 genetic programs and by repressing the opposing Th2 and Th17 genetic programs. Activates transcription of a set of genes important for Th1 cell function, including those encoding IFN-gamma and the chemokine receptor CXCR3. Induces permissive chromatin accessibilty and CpG methylation in IFNG. Activates IFNG and CXCR3 genes in part by recruiting chromatin remodeling complexes including KDM6B, a SMARCA4-containing SWI/SNF-complex, and an H3K4me2-methyltransferase complex to their promoters and all of these complexes serve to establish a more permissive chromatin state conducive with transcriptional activation. Can activate Th1 genes also via recruitment of Mediator complex and P-TEFb (composed of CDK9 and CCNT1/cyclin-T1) in the form of the super elongation complex (SEC) to super-enhancers and associated genes in activated Th1 cells. Inhibits the Th17 cell lineage commitment by blocking RUNX1-mediated transactivation of Th17 cell-specific transcriptinal regulator RORC. Inhibits the Th2 cell lineage commitment by suppressing the production of Th2 cytokines, such as IL-4, IL-5, and IL- 13, via repression of transcriptional regulators GATA3 and NFATC2. Protects Th1 cells from amplifying aberrant type-I IFN response in an IFN-gamma abundant microenvironment by acting as a repressor of type-I IFN transcription factors and type-I IFN-stimulated genes. Acts as a regulator of antiviral B-cell responses; controls chronic viral infection by promoting the antiviral antibody IgG2a isotype switching and via regulation of a broad antiviral gene expression program. Required for the correct development of natural killer (NK) and mucosal-associated invariant T (MAIT) cells.
• Tissue Specificity: T-cell specific.
• KEGG Pathway:
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  Inflammatory bowel disease (hsa05321)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 88	DISBJ6JY	Limited	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	T-box transcription factor TBX21 (TBX21) affects the response to substance of Aspirin.	[9]
Budesonide	DMJIBAW	Phase 3 Trial	T-box transcription factor TBX21 (TBX21) increases the response of Budesonide.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-box transcription factor TBX21 (TBX21).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of T-box transcription factor TBX21 (TBX21).	[3]
Dinoprostone	DMTYOPD	Approved	Dinoprostone decreases the expression of T-box transcription factor TBX21 (TBX21).	[4]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of T-box transcription factor TBX21 (TBX21).	[5]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of T-box transcription factor TBX21 (TBX21).	[7]
SGC-CBP30	DMTLRGZ	Investigative	SGC-CBP30 decreases the expression of T-box transcription factor TBX21 (TBX21).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of T-box transcription factor TBX21 (TBX21).	[6]

References

• [1] Human T-bet Governs Innate and Innate-like Adaptive IFN- Immunity against Mycobacteria. Cell. 2020 Dec 23;183(7):1826-1847.e31. doi: 10.1016/j.cell.2020.10.046. Epub 2020 Dec 8.
• [2] Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes. BMC Immunol. 2006 Nov 21;7:27. doi: 10.1186/1471-2172-7-27.
• [3] 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.
• [4] Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med. 2009 Mar 16;206(3):535-48. doi: 10.1084/jem.20082293. Epub 2009 Mar 9.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] 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.
• [7] Molecular events in human T cells treated with diesel exhaust particles or formaldehyde that underlie their diminished interferon-gamma and interleukin-10 production. Int Arch Allergy Immunol. 2009;148(3):239-50. doi: 10.1159/000161584. Epub 2008 Oct 10.
• [8] CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):10768-73. doi: 10.1073/pnas.1501956112. Epub 2015 Aug 10.
• [9] Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet. 2005 Jun;117(1):16-26. doi: 10.1007/s00439-005-1285-0. Epub 2005 Apr 2.
• [10] TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18099-104. doi: 10.1073/pnas.0408532102. Epub 2004 Dec 16.