Review
Copyright ©The Author(s) 2015.
World J Transl Med. Apr 12, 2015; 4(1): 11-24
Published online Apr 12, 2015. doi: 10.5528/wjtm.v4.i1.11
Table 1 Most common chromatin modifications with their reader motifs and function
Chromatin modificationNomenclatureChromatin-reader motifAttributed function
DNA modification
5-methylcytosine5mCMBD domainTranscription
5-formylcytosine5fCUnknownUnknown
5-hydroxymethylcytosine5hmCUnknownTranscription
5-carboxylcytosine5caCUnknownUnknown
Histone modification
AcetylationK-acBromodomainTandem PHD fingersTranscription, repair, replication, and condensation
Methylation (lysine)K-me1, K-me2, K-me3Chromodomain, tudor domain, MBT domain, PWWP domain, PHD fingersTranscription and repair
Methylation (arginine)R-me, R-me2s, R-me2aTudor domainTranscription
Phosphorylation (serine and threonine)S-ph, T-ph14-3-3. BRCTTranscription, repair and condensation
Phosphorylation (tyrosine)Y-phSH2Transcription and repair
UbiquitylationK-ubUIM, IUIMTranscription and repair
SumoylationK-suSIMTranscription and repair
ADP ribosylationE-arMacro domain, PBZ domainTranscription and repair
DeiminationR→CitUnknownTranscription and decondensation
Propoline isomerisationP-cis↔P-transUnknownTranscription
CrotonylationK-crUnknownTranscription
PropionylationK-prUnknownUnknown
ButyrylationK-buUnknownUnknown
FormylationK-foUnknownUnknown
HydroxylationY-ohUnknownUnknown
O-GIcNAcylation (serine and threonine)S-GIcNAc; T-GIcNAcUnknownTranscription
Table 2 Abnormal DNA methylation patterns in cancer cells and related consequences
DNA hypomethylationConsequence
Global hymethylationReactivation of endoparasitic and repetitive genomic sequences Chromosomal and genomic instability
Hypomethylation of gene bodiesActivation of incorrect sites of transcription initiation
Loss of promoter methylationActivation of metastasis and tumour promoting genes
DNA hypermethylationConsequence
Promoter CpG islandTumour-suppressor gene silencing
(CpGI) methylationInhibition of transcription factors suppressors
Loss of imprintingAbnormal transcriptional inactivation Deregulation of imprinted genes
Table 3 Genes that are epigenetically regulated in cancer
Cancer-associated pathwayGene
Cell cycleRb, p16INK4a, p16INK4b, 14-3-3, cyclin E, p14ARF
Signal transductionErbB2, RASSF1, LKB1/STK11, APC
ApoptosisDAPK gene, Caspase-8 gene
DNA repairMGMT, MHL1, BRCA1, FNACF
Carcinogen metabolismGSTP1 gene
Hormonal responseOestrogen receptor gene, progesterone receptor gene, RAR-b2 gene
SenescenceTERT, TERG
Invasion/metastasisTIMP-3 gene, E cadherin gene, VHL gene
TranscriptionRunx3, Twist, Er α, Er β, PR, RAR, vitamin D receptor
Drug responsivenessGlutatione S-transferase, thymidylate synthase
Table 4 Comparison of methylation arrays vs ultra-deep sequencing for DNA methylation analysis
Methylation arraysUltra-deep sequencing
CpG coverage++++
Sensitivity+++++/+ (antibody-based)
Time consuming++++
Data analysis++++
High-throughput++++
Price+++/++ (price decreasing)
Table 5 Epigenetic drug discovery challenges
CategoryIssues
Target selectionFew activating mutations, translocations or syntethic lethal relationships known limited high-quality antibodies to epigenetic proteins and histone marks (e.g., confirm target expression linkage of target to mark) Biology driving cancer phenotype unknown or poorly understood Post-translation modification of histone vs non-histone substrates by "epigenetic" targets unclear
ChemistryExisting chemical librairies may not have adeguate diversity to provide goog strating points Few crystal structures solved; are structrues relevant if not reflecting complete complex?
Assay developmentFew reference compunds to establish assy signal window, sensitivity, reproducibility Are binding or enzyme configured to properly reflect physiological context? Production of actibe enzymes is difficult, may require multimeric complex and specific sunstrate (nucleosome, histone, non-histone) Limited high-quality antibodies to epigenetic proteins and histone marks (quantify mark or target gene product)
In vivo biologyHistone marks and target genes slow to change, require longer-duration studies to assess engagement (PD biomarker) May necessitate higer compund requirement to conduct studies, earlier optimation of PK properties than traditional paradigm May require novel models for tumors with mutation or traslocations
ToxicologyAcute and/or chronic liabilities of specific isofrom targed epigenetic therapies currently unknown Knockout animal data limited; inducibile knockouts, dominant negatives preferred but more scarce and technically challening
ClinicalIdentify and implement appropriate patient selection markers, more challenging if not activating mutation (overexpression, gene profile?) Identify and implement suitable PD marker (posttranslational modification or mark, target gene, surrogate tissue or tumor?) Epigenetic changes at metastatic sites can differ from primary tumor, which should be targed clinically?