Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSP1W0F)

• DOT Name: Mediator of RNA polymerase II transcription subunit 13-like (MED13L)
• Synonyms: Mediator complex subunit 13-like; Thyroid hormone receptor-associated protein 2; Thyroid hormone receptor-associated protein complex 240 kDa component-like
• Gene Name: MED13L
• Related Disease:
  Cardiac anomalies - developmental delay - facial dysmorphism syndrome
  Neurodevelopmental disorder
  Syndromic intellectual disability
  Colon cancer
  Colon carcinoma
  Craniosynostosis
  Crohn disease
  Intellectual disability
  Intellectual disability, autosomal dominant 40
  Isolated Pierre-Robin syndrome
  Language disorder
  Movement disorder
  Transposition of the great arteries
  Cognitive impairment
  Congenital heart disease
  Kleefstra syndrome
  Kleefstra syndrome 1
• UniProt ID: MD13L_HUMAN
• Pfam ID: PF06333 ; PF11597 ; PF18296
• Sequence:
  MTAAANWVANGASLEDCHSNLFSLAELTGIKWRRYNFGGHGDCGPIISAPAQDDPILLSF
  IRCLQANLLCVWRRDVKPDCKELWIFWWGDEPNLVGVIHHELQVVEEGLWENGLSYECRT
  LLFKAIHNLLERCLMDKNFVRIGKWFVRPYEKDEKPVNKSEHLSCAFTFFLHGESNVCTS
  VEIAQHQPIYLINEEHIHMAQSSPAPFQVLVSPYGLNGTLTGQAYKMSDPATRKLIEEWQ
  YFYPMVLKKKEESKEEDELGYDDDFPVAVEVIVGGVRMVYPSAFVLISQNDIPVPQSVAS
  AGGHIAVGQQGLGSVKDPSNCGMPLTPPTSPEQAILGESGGMQSAASHLVSQDGGMITMH
  SPKRSGKIPPKLHNHMVHRVWKECILNRTQSKRSQMSTPTLEEEPASNPATWDFVDPTQR
  VSCSCSRHKLLKRCAVGPNRPPTVSQPGFSAGPSSSSSLPPPASSKHKTAERQEKGDKLQ
  KRPLIPFHHRPSVAEELCMEQDTPGQKLGLAGIDSSLEVSSSRKYDKQMAVPSRNTSKQM
  NLNPMDSPHSPISPLPPTLSPQPRGQETESLDPPSVPVNPALYGNGLELQQLSTLDDRTV
  LVGQRLPLMAEVSETALYCGIRPSNPESSEKWWHSYRLPPSDDAEFRPPELQGERCDAKM
  EVNSESTALQRLLAQPNKRFKIWQDKQPQLQPLHFLDPLPLSQQPGDSLGEVNDPYTFED
  GDIKYIFTANKKCKQGTEKDSLKKNKSEDGFGTKDVTTPGHSTPVPDGKNAMSIFSSATK
  TDVRQDNAAGRAGSSSLTQVTDLAPSLHDLDNIFDNSDDDELGAVSPALRSSKMPAVGTE
  DRPLGKDGRAAVPYPPTVADLQRMFPTPPSLEQHPAFSPVMNYKDGISSETVTALGMMES
  PMVSMVSTQLTEFKMEVEDGLGSPKPEEIKDFSYVHKVPSFQPFVGSSMFAPLKMLPSHC
  LLPLKIPDACLFRPSWAIPPKIEQLPMPPAATFIRDGYNNVPSVGSLADPDYLNTPQMNT
  PVTLNSAAPASNSGAGVLPSPATPRFSVPTPRTPRTPRTPRGGGTASGQGSVKYDSTDQG
  SPASTPSTTRPLNSVEPATMQPIPEAHSLYVTLILSDSVMNIFKDRNFDSCCICACNMNI
  KGADVGLYIPDSSNEDQYRCTCGFSAIMNRKLGYNSGLFLEDELDIFGKNSDIGQAAERR
  LMMCQSTFLPQVEGTKKPQEPPISLLLLLQNQHTQPFASLNFLDYISSNNRQTLPCVSWS
  YDRVQADNNDYWTECFNALEQGRQYVDNPTGGKVDEALVRSATVHSWPHSNVLDISMLSS
  QDVVRMLLSLQPFLQDAIQKKRTGRTWENIQHVQGPLTWQQFHKMAGRGTYGSEESPEPL
  PIPTLLVGYDKDFLTISPFSLPFWERLLLDPYGGHRDVAYIVVCPENEALLEGAKTFFRD
  LSAVYEMCRLGQHKPICKVLRDGIMRVGKTVAQKLTDELVSEWFNQPWSGEENDNHSRLK
  LYAQVCRHHLAPYLATLQLDSSLLIPPKYQTPPAAAQGQATPGNAGPLAPNGSAAPPAGS
  AFNPTSNSSSTNPAASSSASGSSVPPVSSSASAPGISQISTTSSSGFSGSVGGQNPSTGG
  ISADRTQGNIGCGGDTDPGQSSSQPSQDGQESVTERERIGIPTEPDSADSHAHPPAVVIY
  MVDPFTYAAEEDSTSGNFWLLSLMRCYTEMLDNLPEHMRNSFILQIVPCQYMLQTMKDEQ
  VFYIQYLKSMAFSVYCQCRRPLPTQIHIKSLTGFGPAASIEMTLKNPERPSPIQLYSPPF
  ILAPIKDKQTELGETFGEASQKYNVLFVGYCLSHDQRWLLASCTDLHGELLETCVVNIAL
  PNRSRRSKVSARKIGLQKLWEWCIGIVQMTSLPWRVVIGRLGRLGHGELKDWSILLGECS
  LQTISKKLKDVCRMCGISAADSPSILSACLVAMEPQGSFVVMPDAVTMGSVFGRSTALNM
  QSSQLNTPQDASCTHILVFPTSSTIQVAPANYPNEDGFSPNNDDMFVDLPFPDDMDNDIG
  ILMTGNLHSSPNSSPVPSPGSPSGIGVGSHFQHSRSQGERLLSREAPEELKQQPLALGYF
  VSTAKAENLPQWFWSSCPQAQNQCPLFLKASLHHHISVAQTDELLPARNSQRVPHPLDSK
  TTSDVLRFVLEQYNALSWLTCNPATQDRTSCLPVHFVVLTQLYNAIMNIL
• Function: Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.
• Tissue Specificity: Highly expressed in brain (cerebellum), heart (aorta), skeletal muscle, kidney, placenta and peripheral blood leukocytes. Highly expressed in fetal brain.
• KEGG Pathway: Thyroid hormone sig.ling pathway (hsa04919)
• Reactome Pathway:
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac anomalies - developmental delay - facial dysmorphism syndrome	DIS9AKO8	Definitive	Autosomal dominant	[1]
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[2]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[5]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[7]
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	Autosomal dominant	[8]
Isolated Pierre-Robin syndrome	DISVEHG7	Strong	Genetic Variation	[9]
Language disorder	DISTLKP7	Strong	Genetic Variation	[8]
Movement disorder	DISOJJ2D	moderate	Genetic Variation	[9]
Transposition of the great arteries	DISPXJ8X	moderate	Genetic Variation	[10]
Cognitive impairment	DISH2ERD	Disputed	Genetic Variation	[11]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[3]
Kleefstra syndrome	DISHH9SN	Limited	Genetic Variation	[12]
Kleefstra syndrome 1	DISNODDM	Limited	Genetic Variation	[12]

3 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 Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[22]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[23]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[24]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[26]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[28]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mediator of RNA polymerase II transcription subunit 13-like (MED13L).	[33]

References

• [1] Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome. Eur J Hum Genet. 2015 Nov;23(11):1499-504. doi: 10.1038/ejhg.2015.19. Epub 2015 Feb 25.
• [2] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Depletion of Mediator Kinase Module Subunits Represses Superenhancer-Associated Genes in Colon Cancer Cells.Mol Cell Biol. 2018 May 15;38(11):e00573-17. doi: 10.1128/MCB.00573-17. Print 2018 Jun 1.
• [5] MED13L haploinsufficiency syndrome: A de novo frameshift and recurrent intragenic deletions due to parental mosaicism.Am J Med Genet A. 2017 May;173(5):1264-1269. doi: 10.1002/ajmg.a.38168. Epub 2017 Mar 29.
• [6] Mucosal genome-wide methylation changes in inflammatory bowel disease.Inflamm Bowel Dis. 2012 Nov;18(11):2128-37. doi: 10.1002/ibd.22942. Epub 2012 Mar 14.
• [7] Is MED13L-related intellectual disability a recognizable syndrome?.Eur J Med Genet. 2019 Feb;62(2):129-136. doi: 10.1016/j.ejmg.2018.06.014. Epub 2018 Jun 27.
• [8] Redefining the MED13L syndrome. Eur J Hum Genet. 2015 Oct;23(10):1308-17. doi: 10.1038/ejhg.2015.26. Epub 2015 Mar 11.
• [9] MED13L loss-of-function variants in two patients with syndromic Pierre Robin sequence.Am J Med Genet A. 2018 Jan;176(1):181-186. doi: 10.1002/ajmg.a.38536. Epub 2017 Nov 21.
• [10] Increasing evidence of pathogenic role of the Mediator (MED) complex in the development of cardiovascular diseases.Biochimie. 2019 Oct;165:1-8. doi: 10.1016/j.biochi.2019.06.014. Epub 2019 Jun 27.
• [11] Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.J Med Genet. 2014 Nov;51(11):724-36. doi: 10.1136/jmedgenet-2014-102554. Epub 2014 Aug 28.
• [12] Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation.Eur J Med Genet. 2017 Sep;60(9):451-464. doi: 10.1016/j.ejmg.2017.06.004. Epub 2017 Jun 21.
• [13] 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.
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• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] 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.
• [20] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [21] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [22] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [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] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [31] 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.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [33] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.