Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTECRO7N)

• DOT Name: PHD finger protein 12 (PHF12)
• Synonyms: PHD factor 1; Pf1
• Gene Name: PHF12
• Related Disease:
  Paroxysmal familial ventricular fibrillation
  Vibrio cholerae infection
• UniProt ID: PHF12_HUMAN
• PDB ID: 2L9S; 2LKM; 8BPA; 8BPB; 8BPC; 8C60
• Pfam ID: PF00628 ; PF16737
• Sequence:
  MWEKMETKTIVYDLDTSGGLMEQIQALLAPPKTDEAEKRSRKPEKEPRRSGRATNHDSCD
  SCKEGGDLLCCDHCPAAFHLQCCNPPLSEEMLPPGEWMCHRCTVRRKKREQKKELGHVNG
  LVDKSGKRTTSPSSDTDLLDRSASKTELKAIAHARILERRASRPGTPTSSASTETPTSEQ
  NDVDEDIIDVDEEPVAAEPDYVQPQLRRPFELLIAAAMERNPTQFQLPNELTCTTALPGS
  SKRRRKEETTGKNVKKTQHELDHNGLVPLPVKVCFTCNRSCRVAPLIQCDYCPLLFHMDC
  LEPPLTAMPLGRWMCPNHIEHVVLNQKNMTLSNRCQVFDRFQDTVSQHVVKVDFLNRIHK
  KHPPNRRVLQSVKRRSLKVPDAIKSQYQFPPPLIAPAAIRDGELICNGIPEESQMHLLNS
  EHLATQAEQQEWLCSVVALQCSILKHLSAKQMPSHWDSEQTEKADIKPVIVTDSSVTTSL
  QTADKTPTPSHYPLSCPSGISTQNSLSCSPPHQSPALEDIGCSSCAEKSKKTPCGTANGP
  VNTEVKANGPHLYSSPTDSTDPRRLPGANTPLPGLSHRQGWPRPLTPPAAGGLQNHTVGI
  IVKTENATGPSSCPQRSLVPVPSLPPSIPSSCASIENTSTLQRKTVQSQIGPPLTDSRPL
  GSPPNATRVLTPPQAAGDGILATTANQRFSSPAPSSDGKVSPGTLSIGSALTVPSFPANS
  TAMVDLTNSLRAFMDVNGEIEINMLDEKLIKFLALQRIHQLFPSRVQPSPGSVGTHQLAS
  GGHHIEVQRKEVQARAVFYPLLGLGGAVNMCYRTLYIGTGADMDVCLTNYGHCNYVSGKH
  ACIFYDENTKHYELLNYSEHGTTVDNVLYSCDFSEKTPPTPPSSIVAKVQSVIRRRRHQK
  QDEEPSEEAAMMSSQAQGPQRRPCNCKASSSSLIGGSGAGWEGTALLHHGSYIKLGCLQF
  VFSITEFATKQPKGDASLLQDGVLAEKLSLKPHQGPVLRSNSVP
• Function: Transcriptional repressor acting as key scaffolding subunit of SIN3 complexes which contributes to complex assembly by contacting each core subunit domain, stabilizes the complex and constitutes the substrate receptor by recruiting the H3 histone tail. SIN3 complexes are composed of a SIN3 scaffold subunit, one catalytic core (HDAC1 or HDAC2) and 2 chromatin targeting modules. SIN3B complex represses transcription and counteracts the histone acetyltransferase activity of EP300 through the recognition H3K27ac marks by PHF12 and the activity of the histone deacetylase HDAC2. SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription. May also repress transcription in a SIN3A-independent manner through recruitment of functional TLE5 complexes to DNA. May also play a role in ribosomal biogenesis.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Paroxysmal familial ventricular fibrillation	DISRM7IX	Strong	Genetic Variation	[1]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of PHD finger protein 12 (PHF12).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of PHD finger protein 12 (PHF12).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of PHD finger protein 12 (PHF12).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of PHD finger protein 12 (PHF12).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PHD finger protein 12 (PHF12).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of PHD finger protein 12 (PHF12).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of PHD finger protein 12 (PHF12).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of PHD finger protein 12 (PHF12).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of PHD finger protein 12 (PHF12).	[10]

References

• [1] Unique cardiac Purkinje fiber transient outward current -subunit composition: a potential molecular link to idiopathic ventricular fibrillation.Circ Res. 2013 May 10;112(10):1310-22. doi: 10.1161/CIRCRESAHA.112.300227. Epub 2013 Mar 26.
• [2] Molecular typing of Vibrio cholerae O1 isolates from Thailand by pulsed-field gel electrophoresis.J Health Popul Nutr. 2008 Mar;26(1):79-87.
• [3] 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.
• [4] 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.
• [5] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [6] Aberrantly expressed genes in HaCaT keratinocytes chronically exposed to arsenic trioxide. Biomark Insights. 2011 Feb 8;6:7-16.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] 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.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [10] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [11] 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.