Page last updated: 2024-10-24

negative regulation of gene expression via chromosomal CpG island methylation

Definition

Target type: biologicalprocess

An epigenetic gene regulation mechanism that negatively regulates gene expression by methylation of cytosine residues in chromosomal CpG islands. CpG islands are genomic regions that contain a high frequency of the CG dinucleotide associated with the transcription start site of genes. [PMID:11898023, Wikipedia:Cpg_island]

Negative regulation of gene expression via chromosomal CpG island methylation is a complex process involving the addition of a methyl group to cytosine bases within CpG dinucleotides located in CpG islands, which are regions of DNA with a high frequency of CpG dinucleotides. These CpG islands are often found in gene promoter regions, and methylation of these regions can lead to a decrease in gene expression. The process is initiated by DNA methyltransferases (DNMTs), a family of enzymes that catalyze the transfer of a methyl group from S-adenosyl methionine (SAM) to the 5' position of cytosine. DNMTs have a strong preference for hemimethylated CpG dinucleotides, meaning that one strand of the DNA is already methylated, while the other is not. This allows DNMTs to create a symmetrically methylated CpG dinucleotide, which can then be recognized by other proteins involved in gene silencing. Methylation of CpG islands can lead to a decrease in gene expression through several mechanisms. Firstly, methylated CpG islands can recruit methyl-CpG binding domain (MBD) proteins, which can then recruit histone deacetylases (HDACs) to the region. HDACs remove acetyl groups from histone proteins, which leads to a more condensed chromatin structure. This condensed chromatin structure makes it more difficult for transcription factors to access the DNA and initiate transcription. Secondly, methylated CpG islands can also recruit other proteins that block the binding of transcription factors to the DNA. This can also lead to a decrease in gene expression. Finally, methylation of CpG islands can also lead to the recruitment of DNA methyltransferases (DNMTs) to the region, which can then further methylate the DNA, leading to a more stable silenced state. In summary, negative regulation of gene expression via chromosomal CpG island methylation involves the methylation of CpG islands in gene promoter regions by DNMTs. Methylation of CpG islands can recruit MBD proteins, HDACs, and other proteins that block the binding of transcription factors, ultimately leading to a decrease in gene expression. The process is essential for normal development, differentiation, and cell function. Aberrant methylation patterns are associated with various diseases, including cancer.'
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Proteins (9)

ProteinDefinitionTaxonomy
Myc proto-oncogene proteinA c-myc protein that is encoded in the genome of chicken. [OMA:P01109, PRO:DNx]Gallus gallus (chicken)
DNA (cytosine-5)-methyltransferase 3AA DNA (cytosine-5)-methyltransferase 3A that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9Y6K1]Homo sapiens (human)
E3 ubiquitin-protein ligase UHRF1An E3 ubiquitin-protein ligase UHRF1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96T88]Homo sapiens (human)
Histone-lysine N-methyltransferase EHMT2A histone-lysine N-methyltransferase, H3 lysine-9 specific 3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96KQ7]Homo sapiens (human)
Ubiquitin carboxyl-terminal hydrolase 7A ubiquitin carboxyl-terminal hydrolase 7 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q93009]Homo sapiens (human)
Breast cancer type 1 susceptibility proteinA breast cancer type 1 susceptibility protein that is encoded in the genome of human. [PRO:DNx]Homo sapiens (human)
DNA (cytosine-5)-methyltransferase 1A DNA (cytosine-5)-methyltransferase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P26358]Homo sapiens (human)
Myc proto-oncogene proteinA c-myc protein that is encoded in the genome of human. [PRO:CNA, UniProtKB:P01106]Homo sapiens (human)
Protein arginine N-methyltransferase 5A protein arginine N-methyltransferase 5 that is encoded in the genome of human. [PRO:DNx, UniProtKB:O14744]Homo sapiens (human)

Compounds (70)

CompoundDefinitionClassesRoles
aurintricarboxylic acidaurintricarboxylic acid : A member of the class of quinomethanes that is 3-methylidene-6-oxocyclohexa-1,4-diene-1-carboxylic acid in which the methylidene hydrogens are replaced by 4-carboxy-3-hydroxyphenyl groups. The trisodium salt is the biological stain 'chrome violet CG' while the triammonium salt is 'aluminon'.

Aurintricarboxylic Acid: A dye which inhibits protein biosynthesis at the initial stages. The ammonium salt (aluminon) is a reagent for the colorimetric estimation of aluminum in water, foods, and tissues.
monohydroxybenzoic acid;
quinomethanes;
tricarboxylic acid
fluorochrome;
histological dye;
insulin-like growth factor receptor 1 antagonist
disulfiramorganic disulfide;
organosulfur acaricide
angiogenesis inhibitor;
antineoplastic agent;
apoptosis inducer;
EC 1.2.1.3 [aldehyde dehydrogenase (NAD(+))] inhibitor;
EC 3.1.1.1 (carboxylesterase) inhibitor;
EC 3.1.1.8 (cholinesterase) inhibitor;
EC 5.99.1.2 (DNA topoisomerase) inhibitor;
ferroptosis inducer;
fungicide;
NF-kappaB inhibitor
ebselenebselen : A benzoselenazole that is 1,2-benzoselenazol-3-one carrying an additional phenyl substituent at position 2. Acts as a mimic of glutathione peroxidase.benzoselenazoleanti-inflammatory drug;
antibacterial agent;
anticoronaviral agent;
antifungal agent;
antineoplastic agent;
antioxidant;
apoptosis inducer;
EC 1.13.11.33 (arachidonate 15-lipoxygenase) inhibitor;
EC 1.13.11.34 (arachidonate 5-lipoxygenase) inhibitor;
EC 1.3.1.8 [acyl-CoA dehydrogenase (NADP(+))] inhibitor;
EC 1.8.1.12 (trypanothione-disulfide reductase) inhibitor;
EC 2.5.1.7 (UDP-N-acetylglucosamine 1-carboxyvinyltransferase) inhibitor;
EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor;
EC 3.1.3.25 (inositol-phosphate phosphatase) inhibitor;
EC 3.4.22.69 (SARS coronavirus main proteinase) inhibitor;
EC 3.5.4.1 (cytosine deaminase) inhibitor;
EC 5.1.3.2 (UDP-glucose 4-epimerase) inhibitor;
enzyme mimic;
ferroptosis inhibitor;
genotoxin;
hepatoprotective agent;
neuroprotective agent;
radical scavenger
beta-thujaplicinbeta-thujaplicin : A monoterpenoid that is cyclohepta-2,4,6-trien-1-one substituted by a hydroxy group at position 2 and an isopropyl group at position 4. Isolated from Thuja plicata and Chamaecyparis obtusa, it exhibits antimicrobial activities.

beta-thujaplicin: structure
cyclic ketone;
enol;
monoterpenoid
antibacterial agent;
antifungal agent;
antineoplastic agent;
antiplasmodial drug;
plant metabolite
mefenamic acidmefenamic acid : An aminobenzoic acid that is anthranilic acid in which one of the hydrogens attached to the nitrogen is replaced by a 2,3-dimethylphenyl group. Although classed as a non-steroidal anti-inflammatory drug, its anti-inflammatory properties are considered to be minor. It is used to relieve mild to moderate pain, including headaches, dental pain, osteoarthritis and rheumatoid arthritis.

Mefenamic Acid: A non-steroidal anti-inflammatory agent with analgesic, anti-inflammatory, and antipyretic properties. It is an inhibitor of cyclooxygenase.
aminobenzoic acid;
secondary amino compound
analgesic;
antipyretic;
antirheumatic drug;
EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor;
environmental contaminant;
non-steroidal anti-inflammatory drug;
xenobiotic
pentamidinepentamidine : A diether consisting of pentane-1,5-diol in which both hydroxyl hydrogens have been replaced by 4-amidinophenyl groups. A trypanocidal drug that is used for treatment of cutaneous leishmaniasis and Chagas disease.

Pentamidine: Antiprotozoal agent effective in trypanosomiasis, leishmaniasis, and some fungal infections; used in treatment of PNEUMOCYSTIS pneumonia in HIV-infected patients. It may cause diabetes mellitus, central nervous system damage, and other toxic effects.
aromatic ether;
carboxamidine;
diether
anti-inflammatory agent;
antifungal agent;
calmodulin antagonist;
chemokine receptor 5 antagonist;
EC 2.3.1.48 (histone acetyltransferase) inhibitor;
NMDA receptor antagonist;
S100 calcium-binding protein B inhibitor;
trypanocidal drug;
xenobiotic
procainamideprocainamide : A benzamide that is 4-aminobenzamide substituted on the amide N by a 2-(diethylamino)ethyl group. It is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias.

Procainamide: A class Ia antiarrhythmic drug that is structurally-related to PROCAINE.
benzamidesanti-arrhythmia drug;
platelet aggregation inhibitor;
sodium channel blocker
vorinostatvorinostat : A dicarboxylic acid diamide comprising suberic (octanedioic) acid coupled to aniline and hydroxylamine. A histone deacetylase inhibitor, it is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL).

Vorinostat: A hydroxamic acid and anilide derivative that acts as a HISTONE DEACETYLASE inhibitor. It is used in the treatment of CUTANEOUS T-CELL LYMPHOMA and SEZARY SYNDROME.
dicarboxylic acid diamide;
hydroxamic acid
antineoplastic agent;
apoptosis inducer;
EC 3.5.1.98 (histone deacetylase) inhibitor
thiramthiram : An organic disulfide that results from the formal oxidative dimerisation of N,N-dimethyldithiocarbamic acid. It is widely used as a fungicidal seed treatment.

Thiram: A dithiocarbamate chemical, used commercially in the rubber processing industry and as a fungicide. In vivo studies indicate that it inactivates the enzyme GLUTATHIONE REDUCTASE. It has mutagenic activity and may induce chromosomal aberrations.
organic disulfideantibacterial drug;
antifungal agrochemical;
antiseptic drug
cystamine dihydrochloride
cysteaminecysteamine : An amine that consists of an ethane skeleton substituted with a thiol group at C-1 and an amino group at C-2.

Cysteamine: A mercaptoethylamine compound that is endogenously derived from the COENZYME A degradative pathway. The fact that cysteamine is readily transported into LYSOSOMES where it reacts with CYSTINE to form cysteine-cysteamine disulfide and CYSTEINE has led to its use in CYSTINE DEPLETING AGENTS for the treatment of CYSTINOSIS.
amine;
thiol
geroprotector;
human metabolite;
mouse metabolite;
radiation protective agent
gliotoxingliotoxin : A pyrazinoindole with a disulfide bridge spanning a dioxo-substituted pyrazine ring; mycotoxin produced by several species of fungi.

Gliotoxin: A fungal toxin produced by various species of Trichoderma, Gladiocladium fimbriatum, Aspergillus fumigatus, and Penicillium. It is used as an immunosuppressive agent.
dipeptide;
organic disulfide;
organic heterotetracyclic compound;
pyrazinoindole
antifungal agent;
EC 2.5.1.58 (protein farnesyltransferase) inhibitor;
immunosuppressive agent;
mycotoxin;
proteasome inhibitor
9,10-anthraquinone9,10-anthraquinone : An anthraquinone that is anthracene in which positions 9 and 10 have been oxidised to carbonyls.anthraquinone
dichlonedichlone: structure
1,4-naphthoquinone1,4-naphthoquinone : The parent structure of the family of 1,4-naphthoquinones, in which the oxo groups of the quinone moiety are at positions 1 and 4 of the naphthalene ring. Derivatives have pharmacological properties.

naphthoquinone : A polycyclic aromatic ketone metabolite of naphthalene.
1,4-naphthoquinones
azacitidine5-azacytidine : An N-glycosyl-1,3,5-triazine that is 4-amino-1,3,5-triazin-2(1H)-one substituted by a beta-D-ribofuranosyl residue via an N-glycosidic linkage. An antineoplastic agent, it is used in the treatment of myeloid leukaemia.

Azacitidine: A pyrimidine analogue that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent.
N-glycosyl-1,3,5-triazine;
nucleoside analogue
antineoplastic agent
ninhydrinninhydrin : A member of the class of indanones that is indane-1,3-dione bearing two additional hydroxy substituents at position 2.

Ninhydrin: 2,2-Dihydroxy-1H-indene-1,3-(2H)-dione. Reagent toxic to skin and mucus membranes. It is used in chemical assay for peptide bonds, i.e., protein determinations and has radiosensitizing properties.
aromatic ketone;
beta-diketone;
indanones;
ketone hydrate
colour indicator;
human metabolite
methyl redmethyl red : An azo dye consisting of benzoic acid substituted at position 2 by a 4-[(dimethylamino)phenyl]diazenyl group.

methyl red: RN given refers to parent cpd; structure
diphenyldiselenidediphenyldiselenide: structure given in first source
benzeneseleninic acidbenzeneseleninic acid: structure given in first source
sodium selenatesodium selenate : An inorganic sodium salt having selenate as the counterion.inorganic sodium saltanticonvulsant;
EC 3.1.3.48 (protein-tyrosine-phosphatase) inhibitor;
fertilizer
s-adenosylmethionineacylcarnitine: structure in first source

S-adenosyl-L-methioninate : A sulfonium betaine that is a conjugate base of S-adenosyl-L-methionine obtained by the deprotonation of the carboxy group.
sulfonium betainehuman metabolite
ursolic acidhydroxy monocarboxylic acid;
pentacyclic triterpenoid
geroprotector;
plant metabolite
epigallocatechin gallate(-)-epigallocatechin 3-gallate : A gallate ester obtained by the formal condensation of gallic acid with the (3R)-hydroxy group of (-)-epigallocatechin.

epigallocatechin gallate: a steroid 5alpha-reductase inhibitor and antimutagen in green tea (Camellia sinensis)
flavans;
gallate ester;
polyphenol
antineoplastic agent;
antioxidant;
apoptosis inducer;
geroprotector;
Hsp90 inhibitor;
neuroprotective agent;
plant metabolite
2,2'-dipyridyl disulfide2,2'-dipyridyl disulfide: disulfide is an important moiety in this cpd

aldrithiol : A member of the class of pyridines that is pyridine which is substituted by a pyridin-2-yldisulfanediyl group at position 2. It is a reagent used in molecular biology as an oxidizing agent. Also used in peptide synthesis and for detecting thiols.
organic disulfide;
pyridines
oxidising agent
hexamidinehexamidine : A polyether that is the bis(4-guanidinophenyl) ether of hexane-1,6-diol.aromatic ether;
guanidines;
polyether
antimicrobial agent;
antiseptic drug
glutathione disulfideGlutathione Disulfide: A GLUTATHIONE dimer formed by a disulfide bond between the cysteine sulfhydryl side chains during the course of being oxidized.glutathione derivative;
organic disulfide
Escherichia coli metabolite;
mouse metabolite
sinefunginadenosines;
non-proteinogenic alpha-amino acid
antifungal agent;
antimicrobial agent
5,5'-methylenedisalicylic acid5,5'-methylenedisalicylic acid: inhibits attachment of ribosomes to microsomal membranes; RN given refers to parent cpd; structure in first source & Merck Index, 9th ed, #5934
3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine1,2,4-triazines
xestoquinonexestoquinone: structure given in first source; RN given refers to the (S)-isomer; RN for cpd without isomeric designation not available 5/91; isolated from the sea sponge Xestospongia sapra
s-tubercidinylhomocysteine
furamidinefuramidine: RN given refers to parent cpd; WR 199385 refers to di-HCl; pafuramidine is a prodrug of this
6-bromo-3-(bromomethyl)-7-methyl-2,3,7-trichloro-1-octene6-bromo-3-(bromomethyl)-7-methyl-2,3,7-trichloro-1-octene: structure given in first sourcemonoterpenoid;
organobromine compound;
organochlorine compound
algal metabolite;
antineoplastic agent;
marine metabolite
avasimibemonoterpenoid
s-adenosyl-3-thiopropylamineS-adenosyl-3-thiopropylamine : A thioadenosine that is adenosine in which the hydroxy group at C-5' is replaced by a 3-aminopropyl group.

S-adenosyl-3-thiopropylamine: decarboxylated S-adenosylhomocysteine; RN given refers to parent cpd
organic sulfide;
primary amino compound;
thioadenosine
n(4)-adenosyl-n(4)-methyl-2,4-diaminobutanoic acid
bisdethiobis(methylthio)gliotoxinbisdethiobis(methylthio)gliotoxin: structure given in first source; a platelet activating factor antagonist
nsc 401077NSC 401077: inhibits DNA methyltransferase DNMT1; structure in first source
bardoxolone methylmethyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate: structure in first sourcecyclohexenones
s-adenosylhomocysteineS-adenosyl-L-homocysteine : An organic sulfide that is the S-adenosyl derivative of L-homocysteine.

S-Adenosylhomocysteine: 5'-S-(3-Amino-3-carboxypropyl)-5'-thioadenosine. Formed from S-adenosylmethionine after transmethylation reactions.
adenosines;
amino acid zwitterion;
homocysteine derivative;
homocysteines;
organic sulfide
cofactor;
EC 2.1.1.72 [site-specific DNA-methyltransferase (adenine-specific)] inhibitor;
EC 2.1.1.79 (cyclopropane-fatty-acyl-phospholipid synthase) inhibitor;
epitope;
fundamental metabolite
5'-methylthioadenosine5'-methylthioadenosine: structure

5'-S-methyl-5'-thioadenosine : Adenosine with the hydroxy group at C-5' substituted with a methylthio (methylsulfanyl) group.
thioadenosinealgal metabolite;
Escherichia coli metabolite;
human metabolite;
mouse metabolite;
Saccharomyces cerevisiae metabolite
resveratroltrans-resveratrol : A resveratrol in which the double bond has E configuration.resveratrolantioxidant;
phytoalexin;
plant metabolite;
quorum sensing inhibitor;
radical scavenger
decitabine2'-deoxyribonucleoside
ditiocarb sodiumorganic molecular entity
rg108RG108: DNA methyltransferase inhibitor; structure in first sourceindolyl carboxylic acid
p5091P5091: inhibits ubiquitin-specific protease 7; structure in first source
10074-g510074-G5: structure in first source
verticillinsverticillins: 3 antibiotics isolated from imperfect fungus Verticillium: verticillin A, verticillin B (mono-3-hydroxymethyl analog of verticillin A), & verticillin C (differs from verticillin B in that 1 of dioxopiperazine rings has a trisulfide rather than a disulfide bridge; active against gram-positive bacteria & mycobacteria but not against gram-negative bacteria & fungi; RN given refers to cpd with unknown MF; structure (verticillins A & B))
genistein7-hydroxyisoflavonesantineoplastic agent;
EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor;
geroprotector;
human urinary metabolite;
phytoestrogen;
plant metabolite;
tyrosine kinase inhibitor
stilbamidinestilbamidine: RN given refers to parent cpd
azodicarbonamideorganic molecular entity
psammaplin apsammaplin A: isolated from marine sponges Poecillastra and Jaspis; structure in second source
tws 119pyrroles
chetomin
hbx 41108HBX 41,108: inhibits USP7 ubiquitin protease; structure in first source
sgi-1027SGI-1027: inhibits DNA methyltransferase 1; structure in first source
bix 01294piperidines
unc 0638UNC 0638: inhibits lysine methyltransferases G9a and GLP; structure in first sourcequinazolines
unc 03217-(2-(2-(dimethylamino)ethoxy)ethoxy)-6-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine: a G9a antagonist; structure in first sourcequinazolines
(5-bromo-3-pyridinyl)-[4-(1-pyrrolidinyl)-1-piperidinyl]methanonearomatic carboxylic acid;
pyridinemonocarboxylic acid
1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone: a USP7 inhibitor; structure in first source
unc 0631N-(1-(cyclohexylmethyl)piperidin-4-yl)-2-(4-isopropyl-1,4-diazepan-1-yl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine: inhibits protein lysine methyltransferase G9a; structure in first source
epz004777N-glycosyl compound
entecavirbenzamides;
N-acylpiperidine
gsk343GSK343 : A member of the class of indazoles that is 1-isopropyl-1H-indazole-4-carboxamide in which the nitrogen of the carboxamide group is substituted by a (6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl group and in which the indazole ring is substituted at position 6 by a 2-(4-methylpiperazin-1-yl)pyridin-4-yl group. A highly potent and selective EZH2 inhibitor (IC50 = 4 nM).

GSK343: an EZH2 methyltransferase inhibitor
aminopyridine;
indazoles;
N-alkylpiperazine;
N-arylpiperazine;
pyridone;
secondary carboxamide
antineoplastic agent;
apoptosis inducer;
EC 2.1.1.43 (enhancer of zeste homolog 2) inhibitor
brd4770benzimidazoles
6,7-dimethoxy-2-(pyrrolidin-1-yl)-n-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine: a SETD8 inhibitor; structure in first source
kj-pyr-9KJ-Pyr-9: antineoplastic; structure in first source
gsk3235025GSK3235025: an inhibitor of protein arginine methyltransferase-5 (PRMT5); structure in first source