Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9VSD2D)

• DOT Name: Basic leucine zipper transcriptional factor ATF-like (BATF)
• Synonyms: B-cell-activating transcription factor; B-ATF; SF-HT-activated gene 2 protein; SFA-2
• Gene Name: BATF
• Related Disease:
  Arthritis
  Adult T-cell leukemia/lymphoma
  Allergic asthma
  Anaplastic large cell lymphoma
  Asthma
  Autoimmune disease
  B-cell lymphoma
  Colorectal carcinoma
  Hepatitis B virus infection
  HIV infectious disease
  Latent tuberculosis infection
  Lymphoproliferative syndrome
  Multiple sclerosis
  Non-small-cell lung cancer
  Rheumatoid arthritis
  Tuberculosis
  Graft-versus-host disease
  Osteoarthritis
  Chronic hepatitis B virus infection
  Meningitis
  Type-1 diabetes
• UniProt ID: BATF_HUMAN
• Pfam ID: PF00170
• Sequence:
  MPHSSDSSDSSFSRSPPPGKQDSSDDVRRVQRREKNRIAAQKSRQRQTQKADTLHLESED
  LEKQNAALRKEIKQLTEELKYFTSVLNSHEPLCSVLAASTPSPPEVVYSAHAFHQPHVSS
  PRFQP
• Function: AP-1 family transcription factor that controls the differentiation of lineage-specific cells in the immune system: specifically mediates the differentiation of T-helper 17 cells (Th17), follicular T-helper cells (TfH), CD8(+) dendritic cells and class-switch recombination (CSR) in B-cells. Acts via the formation of a heterodimer with JUNB that recognizes and binds DNA sequence 5'-TGA[CG]TCA-3'. The BATF-JUNB heterodimer also forms a complex with IRF4 (or IRF8) in immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-3'), an immune-specific regulatory element, followed by cooperative binding of BATF and IRF4 (or IRF8) and activation of genes. Controls differentiation of T-helper cells producing interleukin-17 (Th17 cells) by binding to Th17-associated gene promoters: regulates expression of the transcription factor RORC itself and RORC target genes such as IL17 (IL17A or IL17B). Also involved in differentiation of follicular T-helper cells (TfH) by directing expression of BCL6 and MAF. In B-cells, involved in class-switch recombination (CSR) by controlling the expression of both AICDA and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (I(H)-C(H)). Following infection, can participate in CD8(+) dendritic cell differentiation via interaction with IRF4 and IRF8 to mediate cooperative gene activation. Regulates effector CD8(+) T-cell differentiation by regulating expression of SIRT1. Following DNA damage, part of a differentiation checkpoint that limits self-renewal of hematopoietic stem cells (HSCs): up-regulated by STAT3, leading to differentiation of HSCs, thereby restricting self-renewal of HSCs.
• Tissue Specificity: Expressed at highest levels in lung, and at lower levels in placenta, liver, kidney, spleen, and peripheral blood. Detected in SW480 colorectal cancer cell line and several hematopoietic tumor cell lines, including Raji Burkitt's lymphoma. Strongly expressed in mature B- and T-lymphocytes. Also expressed in moderate levels in lymph node and appendix and at low levels in thymus and bone marrow .
• KEGG Pathway: PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway: Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Altered Expression	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[2]
Allergic asthma	DISHF0H3	Strong	Altered Expression	[3]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Altered Expression	[4]
Asthma	DISW9QNS	Strong	Altered Expression	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[8]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[9]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[9]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[10]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[12]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[13]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[9]
Graft-versus-host disease	DIS0QADF	moderate	Biomarker	[14]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[15]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Altered Expression	[16]
Meningitis	DISQABAA	Limited	Genetic Variation	[17]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[23]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[25]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Basic leucine zipper transcriptional factor ATF-like (BATF).	[27]

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 decreases the methylation of Basic leucine zipper transcriptional factor ATF-like (BATF).	[26]

References

• [1] BATF regulates collagen-induced arthritis by regulating T helper cell differentiation.Arthritis Res Ther. 2018 Aug 2;20(1):161. doi: 10.1186/s13075-018-1658-0.
• [2] SFA-2, a novel bZIP transcription factor induced by human T-cell leukemia virus type I, is highly expressed in mature lymphocytes.Biochem Biophys Res Commun. 1996 May 6;222(1):164-70. doi: 10.1006/bbrc.1996.0700.
• [3] The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF-like (BATF), regulates lymphocyte- and mast cell-driven immune responses in the setting of allergic asthma.J Allergy Clin Immunol. 2014 Jan;133(1):198-206.e1-9. doi: 10.1016/j.jaci.2013.09.049. Epub 2013 Nov 28.
• [4] The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma.Leukemia. 2018 Sep;32(9):1994-2007. doi: 10.1038/s41375-018-0045-9. Epub 2018 Mar 28.
• [5] B Cell-Activating Transcription Factor Plays a Critical Role in the Pathogenesis of Anti-Major Histocompatibility Complex-Induced Obliterative Airway Disease.Am J Transplant. 2016 Apr;16(4):1173-82. doi: 10.1111/ajt.13595. Epub 2016 Feb 4.
• [6] SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity.Nucleic Acids Res. 2014 Jul;42(12):7591-610. doi: 10.1093/nar/gku451. Epub 2014 May 29.
• [7] Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer.Gut. 2016 Jul;65(7):1139-50. doi: 10.1136/gutjnl-2014-308227. Epub 2015 Apr 2.
• [8] BATF Interference Blocks Th17 Cell Differentiation and Inflammatory Response in Hepatitis B Virus Transgenic Mice.Dig Dis Sci. 2019 Mar;64(3):773-780. doi: 10.1007/s10620-018-5392-x. Epub 2018 Nov 29.
• [9] BATF Potentially Mediates Negative Regulation of PD-1/PD-Ls Pathway on T Cell Functions in Mycobacterium tuberculosis Infection.Front Immunol. 2019 Oct 15;10:2430. doi: 10.3389/fimmu.2019.02430. eCollection 2019.
• [10] Overexpression of Batf induces an apoptotic defect and an associated lymphoproliferative disorder in mice.Cell Death Dis. 2012 May 17;3(5):e310. doi: 10.1038/cddis.2012.49.
• [11] Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.Nature. 2011 Aug 10;476(7359):214-9. doi: 10.1038/nature10251.
• [12] KIAA1211 plays an oncogenic role in human non-small cell lung cancer.J Cancer. 2019 Oct 22;10(26):6747-6753. doi: 10.7150/jca.35951. eCollection 2019.
• [13] Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes.Epigenetics. 2014 Feb;9(2):276-85. doi: 10.4161/epi.27021. Epub 2013 Nov 8.
• [14] BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease.J Clin Invest. 2018 Mar 1;128(3):916-930. doi: 10.1172/JCI89242. Epub 2018 Jan 29.
• [15] Inhibition of BATF/JUN transcriptional activity protects against osteoarthritic cartilage destruction.Ann Rheum Dis. 2017 Feb;76(2):427-434. doi: 10.1136/annrheumdis-2015-208953. Epub 2016 May 4.
• [16] Increased BATF expression is associated with the severity of liver damage in patients with chronic hepatitis B.Clin Exp Med. 2018 May;18(2):263-272. doi: 10.1007/s10238-017-0480-3. Epub 2017 Nov 21.
• [17] Analysis of the sfaX(II) locus in the Escherichia coli meningitis isolate IHE3034 reveals two novel regulatory genes within the promoter-distal region of the main S fimbrial operon.Microb Pathog. 2009 Mar;46(3):150-8. doi: 10.1016/j.micpath.2008.12.001. Epub 2008 Dec 13.
• [18] VSEAMS: a pipeline for variant set enrichment analysis using summary GWAS data identifies IKZF3, BATF and ESRRA as key transcription factors in type 1 diabetes.Bioinformatics. 2014 Dec 1;30(23):3342-8. doi: 10.1093/bioinformatics/btu571. Epub 2014 Aug 27.
• [19] 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.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [24] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.