Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCUK5KZ)

DOT Name Chromodomain Y-like protein (CDYL)
Synonyms CDY-like; Crotonyl-CoA hydratase; EC 4.2.1.-
Gene Name CDYL
Related Disease
Chronic obstructive pulmonary disease ( )
Depression ( )
Epilepsy ( )
Major depressive disorder ( )
Neurodevelopmental disorder ( )
Hepatocellular carcinoma ( )
Small-cell lung cancer ( )
Temporal lobe epilepsy ( )
UniProt ID
CDYL_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2DNT; 2GTR; 7N27
EC Number
4.2.1.-
Pfam ID
PF00385 ; PF00378
Sequence
MTFQASHRSAWGKSRKKNWQYEGPTQKLFLKRNNVSAPDGPSDPSISVSSEQSGAQQPPA
LQVERIVDKRKNKKGKTEYLVRWKGYDSEDDTWEPEQHLVNCEEYIHDFNRRHTEKQKES
TLTRTNRTSPNNARKQISRSTNSNFSKTSPKALVIGKDHESKNSQLFAASQKFRKNTAPS
LSSRKNMDLAKSGIKILVPKSPVKSRTAVDGFQSESPEKLDPVEQGQEDTVAPEVAAEKP
VGALLGPGAERARMGSRPRIHPLVPQVPGPVTAAMATGLAVNGKGTSPFMDALTANGTTN
IQTSVTGVTASKRKFIDDRRDQPFDKRLRFSVRQTESAYRYRDIVVRKQDGFTHILLSTK
SSENNSLNPEVMREVQSALSTAAADDSKLVLLSAVGSVFCCGLDFIYFIRRLTDDRKRES
TKMAEAIRNFVNTFIQFKKPIIVAVNGPAIGLGASILPLCDVVWANEKAWFQTPYTTFGQ
SPDGCSTVMFPKIMGGASANEMLLSGRKLTAQEACGKGLVSQVFWPGTFTQEVMVRIKEL
ASCNPVVLEESKALVRCNMKMELEQANERECEVLKKIWGSAQGMDSMLKYLQRKIDEF
Function
[Isoform 2]: Chromatin reader protein that recognizes and binds histone H3 trimethylated at 'Lys-9', dimethylated at 'Lys-27' and trimethylated at 'Lys-27' (H3K9me3, H3K27me2 and H3K27me3, respectively). Part of multimeric repressive chromatin complexes, where it is required for transmission and restoration of repressive histone marks, thereby preserving the epigenetic landscape. Required for chromatin targeting and maximal enzymatic activity of Polycomb repressive complex 2 (PRC2); acts as a positive regulator of PRC2 activity by bridging the pre-existing histone H3K27me3 and newly recruited PRC2 on neighboring nucleosomes. Acts as a corepressor for REST by facilitating histone-lysine N-methyltransferase EHMT2 recruitment and H3K9 dimethylation at REST target genes for repression. Involved in X chromosome inactivation in females: recruited to Xist RNA-coated X chromosome and facilitates propagation of H3K9me2 by anchoring EHMT2. Promotes EZH2 accumulation and H3K27me3 methylation at DNA double strand breaks (DSBs), thereby facilitating transcriptional repression at sites of DNA damage and homology-directed repair of DSBs. Required for neuronal migration during brain development by repressing expression of RHOA. By repressing the expression of SCN8A, contributes to the inhibition of intrinsic neuronal excitability and epileptogenesis. In addition to acting as a chromatin reader, acts as a hydro-lyase. Shows crotonyl-coA hydratase activity by mediating the conversion of crotonyl-CoA ((2E)-butenoyl-CoA) to beta-hydroxybutyryl-CoA (3-hydroxybutanoyl-CoA), thereby acting as a negative regulator of histone crotonylation. Histone crotonylation is required during spermatogenesis; down-regulation of histone crotonylation by CDYL regulates the reactivation of sex chromosome-linked genes in round spermatids and histone replacement in elongating spermatids. By regulating histone crotonylation and trimethylation of H3K27, may be involved in stress-induced depression-like behaviors, possibly by regulating VGF expression; [Isoform 1]: Not able to recognize and bind histone H3K9me3, histone H3K27me2 and histone H3K27me3, due to the presence of a N-terminal extension that inactivates the chromo domain ; [Isoform 3]: Not able to recognize and bind histone H3K9me3, histone H3K27me2 and histone H3K27me3, due to the absence of the chromo domain. Acts as a negative regulator of isoform 2 by displacing isoform 2 from chromatin.
Tissue Specificity
Expressed in the hippocampus with reduced expression in epileptic tissue compared to normal adjacent tissue (at protein level) . Ubiquitous . Expressed at moderate levels in all tissues examined . Isoform 2: Most abundantly expressed isoform .

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Chronic obstructive pulmonary disease DISQCIRF Strong Genetic Variation [1]
Depression DIS3XJ69 Strong Biomarker [2]
Epilepsy DISBB28L Strong Biomarker [3]
Major depressive disorder DIS4CL3X Strong Biomarker [2]
Neurodevelopmental disorder DIS372XH moderate Biomarker [4]
Hepatocellular carcinoma DIS0J828 Limited Biomarker [5]
Small-cell lung cancer DISK3LZD Limited Biomarker [6]
Temporal lobe epilepsy DISNOPXX Limited Biomarker [7]
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⏷ Show the Full List of 8 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
12 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 Chromodomain Y-like protein (CDYL). [8]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Chromodomain Y-like protein (CDYL). [9]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Chromodomain Y-like protein (CDYL). [10]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Chromodomain Y-like protein (CDYL). [11]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Chromodomain Y-like protein (CDYL). [13]
Cannabidiol DM0659E Approved Cannabidiol increases the expression of Chromodomain Y-like protein (CDYL). [14]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Chromodomain Y-like protein (CDYL). [15]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Chromodomain Y-like protein (CDYL). [16]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Chromodomain Y-like protein (CDYL). [18]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Chromodomain Y-like protein (CDYL). [20]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of Chromodomain Y-like protein (CDYL). [21]
Coumestrol DM40TBU Investigative Coumestrol decreases the expression of Chromodomain Y-like protein (CDYL). [22]
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⏷ Show the Full List of 12 Drug(s)
4 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of Chromodomain Y-like protein (CDYL). [12]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of Chromodomain Y-like protein (CDYL). [17]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Chromodomain Y-like protein (CDYL). [19]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of Chromodomain Y-like protein (CDYL). [19]
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References

1 Genome-wide association study of smoking behaviours in patients with COPD.Thorax. 2011 Oct;66(10):894-902. doi: 10.1136/thoraxjnl-2011-200154. Epub 2011 Jun 16.
2 Chromodomain Y-like Protein-Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors.Biol Psychiatry. 2019 Apr 15;85(8):635-649. doi: 10.1016/j.biopsych.2018.11.025. Epub 2018 Dec 5.
3 Genome-wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug-resistant epilepsy.Epilepsia. 2018 Aug;59(8):1557-1566. doi: 10.1111/epi.14516. Epub 2018 Jul 16.
4 CDYL Deficiency Disrupts Neuronal Migration and Increases Susceptibility to Epilepsy.Cell Rep. 2017 Jan 10;18(2):380-390. doi: 10.1016/j.celrep.2016.12.043.
5 A Noncoding Regulatory RNAs Network Driven by Circ-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma.Hepatology. 2020 Jan;71(1):130-147. doi: 10.1002/hep.30795. Epub 2019 Aug 11.
6 CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter.Theranostics. 2019 Jul 9;9(16):4717-4729. doi: 10.7150/thno.33680. eCollection 2019.
7 CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression.Nat Commun. 2017 Aug 25;8(1):355. doi: 10.1038/s41467-017-00368-z.
8 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.
9 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
10 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
11 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
12 Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
13 Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
14 Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
15 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
16 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.
17 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.
18 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.
19 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.
20 Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
21 Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
22 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.