Details of Drug Off-Target (DOT)

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

• DOT Name: Zinc finger protein DPF3 (DPF3)
• Synonyms: BRG1-associated factor 45C; BAF45C; Zinc finger protein cer-d4
• Gene Name: DPF3
• Related Disease:
  Age-related macular degeneration
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Male infertility
  Renal cell carcinoma
  Clear cell renal carcinoma
  Familial atrial fibrillation
  Hirschsprung disease
  Small lymphocytic lymphoma
• UniProt ID: DPF3_HUMAN
• PDB ID: 2KWJ; 2KWK; 2KWN; 2KWO; 5I3L; 5SZB; 5SZC
• Pfam ID: PF14051 ; PF00628
• Sequence:
  MATVIHNPLKALGDQFYKEAIEHCRSYNSRLCAERSVRLPFLDSQTGVAQNNCYIWMEKR
  HRGPGLAPGQLYTYPARCWRKKRRLHPPEDPKLRLLEIKPEVELPLKKDGFTSESTTLEA
  LLRGEGVEKKVDAREEESIQEIQRVLENDENVEEGNEEEDLEEDIPKRKNRTRGRARGSA
  GGRRRHDAASQEDHDKPYVCDICGKRYKNRPGLSYHYAHTHLASEEGDEAQDQETRSPPN
  HRNENHRPQKGPDGTVIPNNYCDFCLGGSNMNKKSGRPEELVSCADCGRSGHPTCLQFTL
  NMTEAVKTYKWQCIECKSCILCGTSENDDQLLFCDDCDRGYHMYCLNPPVAEPPEGSWSC
  HLCWELLKEKASAFGCQA
• Function: Belongs to the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. Muscle-specific component of the BAF complex, a multiprotein complex involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Specifically binds acetylated lysines on histone 3 and 4 (H3K14ac, H3K9ac, H4K5ac, H4K8ac, H4K12ac, H4K16ac). In the complex, it acts as a tissue-specific anchor between histone acetylations and methylations and chromatin remodeling. It thereby probably plays an essential role in heart and skeletal muscle development; [Isoform 2]: Acts as a regulator of myogenesis in cooperation with HDGFL2. Mediates the interaction of HDGFL2 with the BAF complex. HDGFL2-DPF3a activate myogenic genes by increasing chromatin accessibility through recruitment of SMARCA4/BRG1/BAF190A (ATPase subunit of the BAF complex) to myogenic gene promoters.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Thermogenesis (hsa04714)
  Hepatocellular carcinoma (hsa05225)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[4]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[5]
Clear cell renal carcinoma	DISBXRFJ	moderate	Genetic Variation	[5]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[2]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[6]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Zinc finger protein DPF3 (DPF3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Zinc finger protein DPF3 (DPF3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Zinc finger protein DPF3 (DPF3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Zinc finger protein DPF3 (DPF3).	[11]

2 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 increases the methylation of Zinc finger protein DPF3 (DPF3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Zinc finger protein DPF3 (DPF3).	[13]

References

• [1] Genome-wide analysis of disease progression in age-related macular degeneration.Hum Mol Genet. 2018 Mar 1;27(5):929-940. doi: 10.1093/hmg/ddy002.
• [2] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [3] Downregulation of DPF3 promotes the proliferation and motility of breast cancer cells through activating JAK2/STAT3 signaling.Biochem Biophys Res Commun. 2019 Jun 30;514(3):639-644. doi: 10.1016/j.bbrc.2019.04.170. Epub 2019 May 7.
• [4] Association of TUSC1 and DPF3 gene polymorphisms with male infertility.J Assist Reprod Genet. 2018 Feb;35(2):257-263. doi: 10.1007/s10815-017-1052-x. Epub 2017 Oct 3.
• [5] Sex specific associations in genome wide association analysis of renal cell carcinoma.Eur J Hum Genet. 2019 Oct;27(10):1589-1598. doi: 10.1038/s41431-019-0455-9. Epub 2019 Jun 23.
• [6] Expression profiles of HA117 and its neighboring gene DPF3 in different colon segments of Hirschsprung's disease.Int J Clin Exp Pathol. 2014 Jun 15;7(7):3966-74. eCollection 2014.
• [7] Identification of a STAT5 target gene, Dpf3, provides novel insights in chronic lymphocytic leukemia.PLoS One. 2013 Oct 14;8(10):e76155. doi: 10.1371/journal.pone.0076155. eCollection 2013.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] 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.