Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTREZK68)

• DOT Name: Methyl-CpG-binding protein 2 (MECP2)
• Synonyms: MeCp-2 protein; MeCp2
• Gene Name: MECP2
• Related Disease:
  Chromosome Xq28 duplication syndrome
  Rett syndrome
  Severe neonatal-onset encephalopathy with microcephaly
  Syndromic X-linked intellectual disability Lubs type
  X-linked intellectual disability-psychosis-macroorchidism syndrome
  Atypical Rett syndrome
  Non-syndromic X-linked intellectual disability
• UniProt ID: MECP2_HUMAN
• PDB ID: 1QK9; 3C2I; 5BT2; 6C1Y; 6OGJ; 6OGK; 6YWW; 8AJR; 8ALQ
• Pfam ID: PF01429
• Sequence:
  MVAGMLGLREEKSEDQDLQGLKDKPLKFKKVKKDKKEEKEGKHEPVQPSAHHSAEPAEAG
  KAETSEGSGSAPAVPEASASPKQRRSIIRDRGPMYDDPTLPEGWTRKLKQRKSGRSAGKY
  DVYLINPQGKAFRSKVELIAYFEKVGDTSLDPNDFDFTVTGRGSPSRREQKPPKKPKSPK
  APGTGRGRGRPKGSGTTRPKAATSEGVQVKRVLEKSPGKLLVKMPFQTSPGGKAEGGGAT
  TSTQVMVIKRPGRKRKAEADPQAIPKKRGRKPGSVVAAAAAEAKKKAVKESSIRSVQETV
  LPIKKRKTRETVSIEVKEVVKPLLVSTLGEKSGKGLKTCKSPGRKSKESSPKGRSSSASS
  PPKKEHHHHHHHSESPKAPVPLLPPLPPPPPEPESSEDPTSPPEPQDLSSSVCKEEKMPR
  GGSLESDGCPKEPAKTQPAVATAATAAEKYKHRGEGERKDIVSSSMPRPNREEPVDSRTP
  VTERVS
• Function: Chromosomal protein that binds to methylated DNA. It can bind specifically to a single methyl-CpG pair. It is not influenced by sequences flanking the methyl-CpGs. Mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A. Binds both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC)-containing DNA, with a preference for 5-methylcytosine (5mC).
• Tissue Specificity: Present in all adult somatic tissues tested.
• Reactome Pathway:
  Loss of MECP2 binding ability to 5hmC-DNA (R-HSA-9022534)
  Loss of phosphorylation of MECP2 at T308 (R-HSA-9022535)
  Loss of MECP2 binding ability to the NCoR/SMRT complex (R-HSA-9022537)
  Loss of MECP2 binding ability to 5mC-DNA (R-HSA-9022538)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  MECP2 regulates neuronal receptors and channels (R-HSA-9022699)
  MECP2 regulates transcription of neuronal ligands (R-HSA-9022702)
  MECP2 regulates transcription factors (R-HSA-9022707)
  MECP2 regulates transcription of genes involved in GABA signaling (R-HSA-9022927)
  Nuclear events stimulated by ALK signaling in cancer (R-HSA-9725371)
  Transcriptional Regulation by MECP2 (R-HSA-8986944)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chromosome Xq28 duplication syndrome	DIS5FMH4	Definitive	X-linked recessive	[1]
Rett syndrome	DISGG5UV	Definitive	X-linked	[2]
Severe neonatal-onset encephalopathy with microcephaly	DISN5P3O	Definitive	X-linked	[3]
Syndromic X-linked intellectual disability Lubs type	DISJ54F6	Definitive	X-linked	[4]
X-linked intellectual disability-psychosis-macroorchidism syndrome	DISG2IRT	Definitive	X-linked recessive	[4]
Atypical Rett syndrome	DISWF699	Supportive	Autosomal dominant	[5]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Methyl-CpG-binding protein 2 (MECP2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Methyl-CpG-binding protein 2 (MECP2).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Methyl-CpG-binding protein 2 (MECP2).	[18]

10 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 Methyl-CpG-binding protein 2 (MECP2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Methyl-CpG-binding protein 2 (MECP2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Methyl-CpG-binding protein 2 (MECP2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Methyl-CpG-binding protein 2 (MECP2).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Methyl-CpG-binding protein 2 (MECP2).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Methyl-CpG-binding protein 2 (MECP2).	[13]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Methyl-CpG-binding protein 2 (MECP2).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Methyl-CpG-binding protein 2 (MECP2).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Methyl-CpG-binding protein 2 (MECP2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Methyl-CpG-binding protein 2 (MECP2).	[17]

References

• [1] Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features. J Med Genet. 2018 Jun;55(6):359-371. doi: 10.1136/jmedgenet-2017-104956. Epub 2018 Apr 4.
• [2] 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.
• [3] MECP2 mutation in non-fatal, non-progressive encephalopathy in a male. J Med Genet. 2001 Mar;38(3):171-4. doi: 10.1136/jmg.38.3.171.
• [4] Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediatr Neurol. 2003;7(1):5-12. doi: 10.1016/s1090-3798(02)00134-4.
• [5] MECP2 Disorders. 2001 Oct 3 [updated 2019 Sep 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [6] MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet. 2001 Apr 15;10(9):941-6. doi: 10.1093/hmg/10.9.941.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Effects of chronic exposure to arsenic and estrogen on epigenetic regulatory genes expression and epigenetic code in human prostate epithelial cells. PLoS One. 2012;7(8):e43880. doi: 10.1371/journal.pone.0043880. Epub 2012 Aug 27.
• [11] LINE-1 gene hypomethylation and p16 gene hypermethylation in HepG2 cells induced by low-dose and long-term triclosan exposure: The role of hydroxyl group. Toxicol In Vitro. 2016 Aug;34:35-44. doi: 10.1016/j.tiv.2016.03.002. Epub 2016 Mar 10.
• [12] 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.
• [13] Expression of DNA methyltransferases in breast cancer patients and to analyze the effect of natural compounds on DNA methyltransferases and associated proteins. J Breast Cancer. 2013 Mar;16(1):23-31. doi: 10.4048/jbc.2013.16.1.23. Epub 2013 Mar 31.
• [14] Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. 2004 Jul-Aug;6(4):354-63. doi: 10.1593/neo.03478.
• [15] 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.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [18] 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.