Mechanisms of transcriptional repression by DNA methylation

Tumorigenesisisknowntobeamultistepprocessinwhichdefectsinvariouscancergenesaccumulate.Epigeneticmodifications,mostimportantlyDNAmethylationevents,arefrequentlyinvolvedintranscriptionalchangesinbothtumorsuppressorgenesandoncogenes.MethylationofcytosineatCpGdinucleotidesisacommonfeatureofahighereukaryoticgenomes.DNAmethylationinthepromoterregionsofgenesisgenerallycorrelatedwithgenesilencing.Twounderlyingmechanismshavebeenidentified.First,bindingoftranscriptionfactorsorenhancerblockingelements,suchasCTCF,maybeinhibitedbyDNAmethylation.ThesecondandmoregeneralmechanisminvolvesproteinsthatdetectmethylatedDNAthroughmethylCpG-bindingdomains(MBDs).Fouroftheseproteins桵BD1,MBD2,MBD3,andMeCP2梙avebeenimplicatedinmethylation-dependentrepressionoftranscription.Theseproteinsmediaterecruitmentofrepressorcomplexesthatincludehistonedeacetylases(HDACs).HDACsremoveacetylgroupsfromlysineresiduesofhistonesH3andH4thatresultsincondensationofchromatinandthuslimitaccessoftranscriptionfactorstopromoterregionsofgeneslocalizednearby.Well-studiedco-repressorcomplexesincludeSin3AandMi-2/NuRD.MeCP2,apolypeptidecharacterizedbyanMBDandatranscriptionalrepressiondomainthatspecificallybindsmethylatedDNA,copurifieswiththeSin3A/HDACcorepressorcomplex.MeCP1complexiscomposedof10majorpolypeptidesincludingMBD2andalloftheknownNuRDcomplexcomponents.Thetwoproteincomplexessharefourpolypeptides:HDAC1,HDAC2,RbAp46,andRbAp48.Inaddition,eachcomplexcontainsuniquepolypeptides(Sin3A,SAP30,andSAP18intheSin3complex,andMi2,MTA1,MTA2andMBD3intheNuRDcomplex).TheNuRDcomplexpossessesnucleosomeremodelingactivitybecauseofthepresenceofMi2,amemberoftheSWI2/SNF2helicase/ATPasefamily.Thiscomplexpreferentiallybinds,remodels,anddeacetylatesmethylatednucleosomes.MTA1orMTA2(metastasis-associatedprotein1or2)expressionlevelsareelevatedinmetastaticcancercells,MTA2modulatestheenzymaticactivityofthehistonedeacetylasecorecomplex.

Contributor:A.Konev,PhD

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