Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS7A6AF)

• DOT Name: Chromodomain-helicase-DNA-binding protein 8 (CHD8)
• Synonyms: CHD-8; EC 3.6.4.12; ATP-dependent helicase CHD8; Helicase with SNF2 domain 1
• Gene Name: CHD8
• Related Disease:
  Complex neurodevelopmental disorder
  Acute myelogenous leukaemia
  Advanced cancer
  Autism
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  CHARGE syndrome
  Colorectal carcinoma
  Gastric cancer
  Haematological malignancy
  Intellectual developmental disorder with autism and macrocephaly
  Intellectual disability
  Metastatic malignant neoplasm
  Metastatic prostate carcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Pervasive developmental disorder
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Stomach cancer
  Stroke
  Isolated congenital microcephaly
  Keratosis pilaris atrophicans
  Neurodevelopmental disorder
  Congenital myasthenic syndrome
  Megalencephaly
  Overgrowth syndrome
• UniProt ID: CHD8_HUMAN
• PDB ID: 2CKA; 2DL6
• EC Number: 3.6.4.12
• Pfam ID: PF07533 ; PF00385 ; PF00271 ; PF00176
• Sequence:
  MADPIMDLFDDPNLFGLDSLTDDSFNQVTQDPIEEALGLPSSLDSLDQMNQDGGGGDVGN
  SSASELVPPPEETAPTELSKESTAPAPESITLHDYTTQPASQEQPAQPVLQTSTPTSGLL
  QVSKSQEILSQGNPFMGVSATAVSSSSAGGQPPQSAPKIVILKAPPSSSVTGAHVAQIQA
  QGITSTAQPLVAGTANGGKVTFTKVLTGTPLRPGVSIVSGNTVLAAKVPGNQAAVQRIVQ
  PSRPVKQLVLQPVKGSAPAGNPGATGPPLKPAVTLTSTPTQGESKRITLVLQQPQSGGPQ
  GHRHVVLGSLPGKIVLQGNQLAALTQAKNAQGQPAKVVTIQLQVQQPQQKIQIVPQPPSS
  QPQPQQPPSTQPVTLSSVQQAQIMGPGQSPGQRLSVPVKVVLQPQAGSSQGASSGLSVVK
  VLSASEVAALSSPASSAPHSGGKTGMEENRRLEHQKKQEKANRIVAEAIARARARGEQNI
  PRVLNEDELPSVRPEEEGEKKRRKKSAGERLKEEKPKKSKTSGASKTKGKSKLNTITPVV
  GKKRKRNTSSDNSDVEVMPAQSPREDEESSIQKRRSNRQVKRKKYTEDLDIKITDDEEEE
  EVDVTGPIKPEPILPEPVQEPDGETLPSMQFFVENPSEEDAAIVDKVLSMRIVKKELPSG
  QYTEAEEFFVKYKNYSYLHCEWATISQLEKDKRIHQKLKRFKTKMAQMRHFFHEDEEPFN
  PDYVEVDRILDESHSIDKDNGEPVIYYLVKWCSLPYEDSTWELKEDVDEGKIREFKRIQS
  RHPELKRVNRPQASAWKKLELSHEYKNRNQLREYQLEGVNWLLFNWYNRQNCILADEMGL
  GKTIQSIAFLQEVYNVGIHGPFLVIAPLSTITNWEREFNTWTEMNTIVYHGSLASRQMIQ
  QYEMYCKDSRGRLIPGAYKFDALITTFEMILSDCPELREIEWRCVIIDEAHRLKNRNCKL
  LDSLKHMDLEHKVLLTGTPLQNTVEELFSLLHFLEPSQFPSESEFLKDFGDLKTEEQVQK
  LQAILKPMMLRRLKEDVEKNLAPKQETIIEVELTNIQKKYYRAILEKNFSFLSKGAGHTN
  MPNLLNTMMELRKCCNHPYLINGAEEKILTEFREACHIIPHDFHLQAMVRSAGKLVLIDK
  LLPKLKAGGHKVLIFSQMVRCLDILEDYLIQRRYLYERIDGRVRGNLRQAAIDRFSKPDS
  DRFVFLLCTRAGGLGINLTAADTCIIFDSDWNPQNDLQAQARCHRIGQSKAVKVYRLITR
  NSYEREMFDKASLKLGLDKAVLQSMSGRDGNITGIQQFSKKEIEDLLRKGAYAAIMEEDD
  EGSKFCEEDIDQILLRRTTTITIESEGKGSTFAKASFVASENRTDISLDDPNFWQKWAKK
  ADLDMDLLNSKNNLVIDTPRVRKQTRHFSTLKDDDLVEFSDLESEDDERPRSRRHDRHHA
  YGRTDCFRVEKHLLVYGWGRWRDILSHGRFKRRMTERDVETICRAILVYCLLHYRGDENI
  KGFIWDLISPAENGKTKELQNHSGLSIPVPRGRKGKKVKSQSTFDIHKADWIRKYNPDTL
  FQDESYKKHLKHQCNKVLLRVRMLYYLRQEVIGDQAEKVLGGAIASEIDIWFPVVDQLEV
  PTTWWDSEADKSLLIGVFKHGYEKYNTMRADPALCFLEKAGRPDDKAIAAEHRVLDNFSD
  IVEGVDFDKDCEDPEYKPLQGPPKDQDDEGDPLMMMDEEISVIDGDEAQVTQQPGHLFWP
  PGSALTARLRRLVTAYQRSYKREQMKIEAAERGDRRRRRCEAAFKLKEIARREKQQRWTR
  REQTDFYRVVSTFGVEYDPDTMQFHWDRFRTFARLDKKTDESLTKYFHGFVAMCRQVCRL
  PPAAGDEPPDPNLFIEPITEERASRTLYRIELLRRLREQVLCHPLLEDRLALCQPPGPEL
  PKWWEPVRHDGELLRGAARHGVSQTDCNIMQDPDFSFLAARMNYMQNHQAGAPAPSLSRC
  STPLLHQQYTSRTASPLPLRPDAPVEKSPEETATQVPSLESLTLKLEHEVVARSRPTPQD
  YEMRVSPSDTTPLVSRSVPPVKLEDEDDSDSELDLSKLSPSSSSSSSSSSSSSSTDESED
  EKEEKLTDQSRSKLYDEESLLSLTMSQDGFPNEDGEQMTPELLLLQERQRASEWPKDRVL
  INRIDLVCQAVLSGKWPSSRRSQEMVTGGILGPGNHLLDSPSLTPGEYGDSPVPTPRSSS
  AASMAEEEASAVSTAAAQFTKLRRGMDEKEFTVQIKDEEGLKLTFQKHKLMANGVMGDGH
  PLFHKKKGNRKKLVELEVECMEEPNHLDVDLETRIPVINKVDGTLLVGEDAPRRAELEMW
  LQGHPEFAVDPRFLAYMEDRRKQKWQRCKKNNKAELNCLGMEPVQTANSRNGKKGHHTET
  VFNRVLPGPIAPESSKKRARRMRPDLSKMMALMQGGSTGSLSLHNTFQHSSSGLQSVSSL
  GHSSATSASLPFMPFVMGGAPSSPHVDSSTMLHHHHHHPHPHHHHHHHPGLRAPGYPSSP
  VTTASGTTLRLPPLQPEEDDDEDEEDDDDLSQGYDSSERDFSLIDDPMMPANSDSSEDAD
  D
• Function: DNA helicase that acts as a chromatin remodeling factor and regulates transcription. Acts as a transcription repressor by remodeling chromatin structure and recruiting histone H1 to target genes. Suppresses p53/TP53-mediated apoptosis by recruiting histone H1 and preventing p53/TP53 transactivation activity. Acts as a negative regulator of Wnt signaling pathway by regulating beta-catenin (CTNNB1) activity. Negatively regulates CTNNB1-targeted gene expression by being recruited specifically to the promoter regions of several CTNNB1 responsive genes. Involved in both enhancer blocking and epigenetic remodeling at chromatin boundary via its interaction with CTCF. Acts as a suppressor of STAT3 activity by suppressing the LIF-induced STAT3 transcriptional activity. Also acts as a transcription activator via its interaction with ZNF143 by participating in efficient U6 RNA polymerase III transcription. Regulates alternative splicing of a core group of genes involved in neuronal differentiation, cell cycle and DNA repair. Enables H3K36me3-coupled transcription elongation and co-transcriptional RNA processing likely via interaction with HNRNPL.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Autosomal dominant	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
CHARGE syndrome	DISKD3CW	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[8]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[9]
Haematological malignancy	DISCDP7W	Strong	Altered Expression	[10]
Intellectual developmental disorder with autism and macrocephaly	DISI09ND	Strong	Autosomal dominant	[11]
Intellectual disability	DISMBNXP	Strong	Autosomal dominant	[12]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[13]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[15]
Obesity	DIS47Y1K	Strong	Genetic Variation	[15]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[14]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[17]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[9]
Stroke	DISX6UHX	Strong	Biomarker	[6]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[18]
Keratosis pilaris atrophicans	DISD96XN	moderate	Genetic Variation	[19]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[20]
Congenital myasthenic syndrome	DISJLG2T	Limited	Autosomal dominant	[12]
Megalencephaly	DISYW5SV	Limited	Genetic Variation	[21]
Overgrowth syndrome	DISHK54G	Limited	Biomarker	[22]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorpyrifos	DMKPUI6	Investigative	Chromodomain-helicase-DNA-binding protein 8 (CHD8) affects the response to substance of Chlorpyrifos.	[31]
Chlorphrifos oxon	DMGBT68	Investigative	Chromodomain-helicase-DNA-binding protein 8 (CHD8) affects the response to substance of Chlorphrifos oxon.	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[24]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[29]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[30]

3 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 Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Chromodomain-helicase-DNA-binding protein 8 (CHD8).	[28]

References

• [1] 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.
• [2] NSD3-Short Is an Adaptor Protein that Couples BRD4 to the CHD8 Chromatin Remodeler.Mol Cell. 2015 Dec 17;60(6):847-59. doi: 10.1016/j.molcel.2015.10.033. Epub 2015 Nov 25.
• [3] Identification of common differentially-expressed miRNAs in ovarian cancer cells and their exosomes compared with normal ovarian surface epithelial cell cells.Oncol Lett. 2018 Aug;16(2):2391-2401. doi: 10.3892/ol.2018.8954. Epub 2018 Jun 12.
• [4] Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science. 2012 Dec 21;338(6114):1619-22. doi: 10.1126/science.1227764. Epub 2012 Nov 15.
• [5] Panel sequencing of 264 candidate susceptibility genes and segregation analysis in a cohort of non-BRCA1, non-BRCA2 breast cancer families.Breast Cancer Res Treat. 2017 Dec;166(3):937-949. doi: 10.1007/s10549-017-4469-0. Epub 2017 Aug 24.
• [6] Cheese consumption and risk of cardiovascular disease: a meta-analysis of prospective studies.Eur J Nutr. 2017 Dec;56(8):2565-2575. doi: 10.1007/s00394-016-1292-z. Epub 2016 Aug 12.
• [7] Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8.Proc Natl Acad Sci U S A. 2018 Aug 28;115(35):E8246-E8255. doi: 10.1073/pnas.1802620115. Epub 2018 Aug 14.
• [8] Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators.Gastroenterology. 2014 Feb;146(2):530-38.e5. doi: 10.1053/j.gastro.2013.10.060. Epub 2013 Nov 6.
• [9] CHD8 is an independent prognostic indicator that regulates Wnt/-catenin signaling and the cell cycle in gastric cancer.Oncol Rep. 2013 Sep;30(3):1137-42. doi: 10.3892/or.2013.2597. Epub 2013 Jul 8.
• [10] The Chromatin Regulator CHD8 Is a Context-Dependent Mediator of Cell Survival in Murine Hematopoietic Malignancies.PLoS One. 2015 Nov 20;10(11):e0143275. doi: 10.1371/journal.pone.0143275. eCollection 2015.
• [11] De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012 Apr 4;485(7397):237-41. doi: 10.1038/nature10945.
• [12] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [13] Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times.Gastroenterology. 2018 Jun;154(8):2060-2063.e8. doi: 10.1053/j.gastro.2018.02.026. Epub 2018 Mar 2.
• [14] Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer. Neoplasia. 2014 Dec;16(12):1018-27. doi: 10.1016/j.neo.2014.10.003.
• [15] A case of 14q11.2 microdeletion with autistic features, severe obesity and facial dysmorphisms suggestive of Wolf-Hirschhorn syndrome.Am J Med Genet A. 2014 Jan;164A(1):190-3. doi: 10.1002/ajmg.a.36200. Epub 2013 Nov 15.
• [16] Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants.Clin Epigenetics. 2019 Jul 16;11(1):103. doi: 10.1186/s13148-019-0684-3.
• [17] A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): A case report and literature review.Am J Med Genet A. 2016 May;170A(5):1225-35. doi: 10.1002/ajmg.a.37566. Epub 2016 Jan 20.
• [18] Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.Mol Psychiatry. 2017 Sep;22(9):1282-1290. doi: 10.1038/mp.2017.140. Epub 2017 Jul 25.
• [19] Advanced Whole-Genome Sequencing and Analysis of Fetal Genomes from Amniotic Fluid.Clin Chem. 2018 Apr;64(4):715-725. doi: 10.1373/clinchem.2017.281220. Epub 2018 Mar 15.
• [20] Long term follow-up in a patient with a de novo microdeletion of 14q11.2 involving CHD8.Am J Med Genet A. 2015 Apr;167A(4):837-41. doi: 10.1002/ajmg.a.36957. Epub 2015 Mar 3.
• [21] Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication.Neurogenetics. 2020 Jan;21(1):67-72. doi: 10.1007/s10048-019-00599-w. Epub 2019 Dec 10.
• [22] The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):557-564. doi: 10.1002/ajmg.c.31749. Epub 2019 Nov 13.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer. Neoplasia. 2014 Dec;16(12):1018-27. doi: 10.1016/j.neo.2014.10.003.
• [26] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [27] 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.
• [28] 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.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [31] Gene-Environment Interactions in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres. Environ Health Perspect. 2021 Jul;129(7):77001. doi: 10.1289/EHP8580. Epub 2021 Jul 14.